Molecular mechanisms of the effect of protein-peptide hormones on the target cells.

Molecular mechanisms of the effect of catecholamines and another biological amines on target cells

The survival of multicellular organisms depends on their ability to adapt to a constantly changing environment. Intercellular communication mechanisms are necessary requirements for this adaptation. The nervous system and the endocrine system provide this intercellular, organism- wide communication. The nervous system was originally viewed as providing a fixed communication system, whereas the endocrine system supplied hormones, which are mobile messages. In fact, there is a remarkable convergence of these regulatory systems. For example, neural regulation of the endocrine system is important in the production and secretion of some hormones; many neurotransmitters resemble hormones in their synthesis, transport, and mechanism of action; and many hormones are synthesized in the nervous system.

Endocrine vs. Nervous System

Nervous System	Endocrine System
Neurons release neurotransmitters	Endocrine cells release hormones
A neurotransmitter acts on specific cell right next to it.	Hormones travel to another nearby cell or act on cell in another part of the body.
Neurotransmitters have their effects within milliseconds.	Hormones take minutes or days to have their effects.
The effects of neurotransmitters are short-lived.	The effects of hormones can last hours, days, or years.
Performs short term crisis management	Regulates long term ongoing metabolic function
Neurotransmitter acts on specific cell right next to it.	Hormone can travel to another nearby cell or it can act on another part of the body.

The word “hormone” is derived from a Greek term that means to arouse to activity. As classically defined, a hormone is a substance that is synthesized in one organ and transported by the circulatory system to act on another tissue. They are secreted in response to changes in the environment inside or outside the body. These are released into the extracellular fluid, where they are diffused into the blood stream. The latter carries them from the site of production to the site of action. They act on specific organs called target organs. The blood contains all the hormones but the cells of a target organ can pick up the specific required hormone only and ignore all others. It has been found that the target cell has on its surface or in its cytoplasm a specific protein molecule, called a receptor, which can recognise and pick out the specific hormone capable of action in that cell. The hormone delivers its message to the target cell by changing the shape of the receptor cell and binds to it. The receptors new shape sets up certain changes in the cell such as alteration in permeability, enzyme activity or gene transcription.

http://www.youtube.com/watch?v=kIPYVV4aThM&feature=related

Hormones may stimulate or inhibit specific biological processes in the target organs to modify their activities thus acting as regulators. There is considerable co-ordination between nerves and hormones. Nerves regulate synthesis and release of some hormones. Some times hormones may also influence nerve activities. Thus, hormonal co-ordination plays an important role in regulating body functions.

Calcitonin secreted by thyroid gland regulates the concentration of calcium and phosphorus in the blood. When the concentration of calcium rises in the blood, the secretion of calcitonin is seen which lowers the concentration of calcium and phosphorus in the plasma by decreasing the release for the bones.

Feedback controls

Maintenance of internal chemical environment of the body to a constant is called homeostasis. Hormones play a major role in maintaining homeostasis by their intergrated action and feed back controls.

Feedback control is mostlly negative, rarely positive. In a negative feedback control, synthesis of a hormone slows or halts when its level in the blood rises above normal. Some of examples of feedback control is given below.

Rise of testosterone level in the blood above normal inhibits ICSH secretion by the anterior pituitary lobe. This negative feedback checks oversecretion of testosterone

Hypothalamus in response to some external stimulus, produces a thyrotrophin-releasing hormone for the secretion of thyrotrophic hormone. The thyrotrophin-releasing hormone (TRH) stimulates the anterior pituitary lobe to secrete thyrotrophic hormone. The latter in turn stimulates the thyroid gland to produce thyroxine. If thyroxine is in excess, it exerts an influence on the hypothalamus and anterior pituitary lobe, which then secrete less releasing hormone and thyroid-stimulating hormone (TSH) respectively. A rise in the TSH level in the blood may also exert negative feed back effect on the hypothalmus and retard the secretion of TRH. This restores the normal blood-thyroxine level.

Functions of hormones.

Hormones regulate the following processes:

Growth and differentiation of cells, tissues, and organs These processes include cell proliferation, embryonic development, and sexual differentiation— i. e., processes that require a prolonged time period and involve proteins de novo synthesis. For this reason, mainly steroid hormones which function via transcription regulation are active in this field

Metabolic pathways Metabolic regulation requires rapidly acting mechanisms. Many of the hormones involved therefore regulate interconversion of enzymes. Themain processes subject to hormonal regulation are the uptake and degradation of storage substances (glycogen, fat), metabolic pathways for biosynthesis and degradation of central metabolites (glucose, fatty acids, etc.), and the supply of metabolic energy.

Digestive processes Digestive processes are usually regulated by locally acting peptides (paracrine), but mediators, biogenic amines, and neuropeptides are also involved.

Maintenance of ion concentrations (homeostasis) Concentrations of Na+, K+, and Cl– in body fluids, and the physiological variables dependent on these (e. g. blood pressure), are subject to strict regulation. The principal site of action of the hormones involved is the kidneys, where hormones increase or reduce the resorption of ions and recovery of water. The concentrations of Ca2+ and phosphate, which form the mineral substance of bone and teeth, are also precisely regulated. Many hormones influence the above processes only indirectly by regulating the synthesis and release of other hormones (hormonal hierarchy).

3. Endocrine, paracrine, and autocrine hormone effects.

http://www.youtube.com/watch?v=3LW7TSBcFjE&feature=related

Hormones transfer signals by migrating from heir site of synthesis to their site of action. They are usually transported in the blood. In this case, they are said to have an endocrine effect (example: insulin). By contrast, tissue hormones, the target cells for which are in the immediate vicinity of the glandular cells that produce them, are said to have a paracrine effect (example: gastrointestinal tract hormones). When signal substances also pass effects back to the cells that synthesize them, they are said to have an autocrine effect (example: prostaglandins). Autocrine effects are often found in tumor cells, which stimulate their own proliferation in this way. Insulin,which is formed in the B cells of the pancreas, has both endocrine and paracrine effects. As a hormone with endocrine effects, it regulates glucose and fat metabolism. Via a paracrinemechanism, it inhibits the synthesis and release of glucagon from the neighboring A cells.

Endocrine glands

The endocrine system is made up of glands that produce and secrete hormones, chemical substances produced in the body that regulate the activity of cells or organs. These hormones regulate the body's growth, metabolism (the physical and chemical processes of the body), and sexual development and function. The hormones are released into the bloodstream and may affect one or several organs throughout the body.

The major glands of the endocrine system are the hypothalamus, pituitary, thyroid, parathyroids, adrenals, pineal body, and the reproductive organs (ovaries and testes). The pancreas is also a part of this system; it has a role in hormone production as well as in digestion.

The endocrine system is regulated by feedback in much the same way that a thermostat regulates the temperature in a room. For the hormones that are regulated by the pituitary gland, a signal is sent from the hypothalamus to the pituitary gland in the form of a "releasing hormone," which stimulates the pituitary to secrete a "stimulating hormone" into the circulation.

The stimulating hormone then signals the target gland to secrete its hormone. As the level of this hormone rises in the circulation, the hypothalamus and the pituitary gland shut down secretion of the releasing hormone and the stimulating hormone, which in turn slows the secretion by the target gland. This system results in stable blood concentrations of the hormones that are regulated by the pituitary gland.

Classification of hormones.

The animal organism contains more than 100 hormones and hormone-like substances, which can be classified either according to their structure or according to their function. In chemical terms, most hormones are:

Ø hormones of protein structure: all hormones of anterior pituitary (except ACTH), insulin, parathyroid hormone;

Ø hormones of peptide structure: ACTH, calcitonin, glucagon, hormones of posterior pituitary, factors of hypothalamus, thymozin;

Ø steroid hormones: adrenal cortical steroids, sex hormones;

Ø

Ø hormones - derivatives of amino acid: thyroid hormones, adrenal medulla hormones, epiphysis hormones;

Ø

Ø hormones derivatives of unsaturated fatty acid: prostaglandins.

Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from

v Lipotrophic

v Hydrophilic

http://www.youtube.com/watch?v=kIPYVV4aThM&feature=related

http://www.youtube.com/watch?v=8fh2HmdxQjQ&feature=related

Mechanism of action

A. Mechanism of action of lipophilic hormones

Lipophilic signaling substances include the steroid hormones, calcitriol, the iodothyronines (T3 and T4), and retinoic acid. These hormones mainly act in the nucleus of the target cells, where they regulate gene transcription in collaboration with their receptors and with the support of additional proteins (known as coactivators and mediators). There are several effects of steroid hormones that are notmediated by transcription control. These alternative pathways for steroid effects have not yet been fully explained. In the blood, there are a number of transport proteins for lipophilic hormones. Only the free hormone is able to penetrate the membrane and enter the cell. The hormone encounters its receptor in the nucleus (and sometimes also in the cytoplasm). The receptors for lipophilic hormones are rare proteins. They occur in small numbers (103–104 molecules per cell) and show marked specificity and high affinity for the hormone (Kd = 10–8–10–10 M). After binding to the hormone, the steroid receptors are able to bind as homodimers or heterodimers to control elements in the promoters of specific genes, from where they can influence the transcription of the affected genes—i. e., they act as transcription factors. The illustration shows the particularly well-investigated mechanism of action for cortisol, which is unusual to the extent that the hormone–receptor complex already arises in the cytoplasm. The free receptor is present in the cytoplasm as a monomer in complex with the chaperone hsp90. Binding of cortisol to the complex leads to an allosteric conformational change in the receptor, which is then released from the hsp90 and becomes capable of DNA binding as a result of dimerization. In the nucleus, the hormone–receptor complex binds to nucleotide sequences known as hormone response elements (HREs).

The second mechanism involves steroid hormones, which pass through the plasma membrane and act in a two step process. Steroid hormones bind, once inside the cell, to the nuclear membrane receptors, producing an activated hormone-receptor complex. The activated hormone-receptor complex binds to DNA and activates specific genes, increasing production of proteins.

These are short palindromic DNA segments that usually promote transcription as enhancer elements. The illustration shows the HRE for glucocorticoids (GRE; “n” stands for any nucleotide). Each hormone receptor only recognizes its “own” HRE and therefore only influences the transcription of genes containing that HRE. Recognition between the receptor and HRE is based on interaction between the amino acid residues in the DNA-binding domain (B) and the relevant bases in the HRE (emphasized in color in the structure illustrated). As discussed on p. 244, the hormone receptor does not interact directly with the RNA polymerase, but rather—along with other transcription factors—with a coactivator/mediator complex that processes all of the signals and passes them on to the polymerase. In this way, hormonal effects lead within a period of minutes to hours to altered levels ofmRNAs for key proteins in cellular processes (“cellular response”).

B. Mechanism of action of hydrophilic hormones

The hormones are released in very small quantities, yet they can cause widespread dresponses in cells or tissues all over the body. These responses in cells or tissues all over the body. These responses can be quite specific and selective in different cells. All vertebrate hormones belong to one of four chemical groups. Some hormones, such hormone, such as adrenaline and thyroid hormone, are small molecules derived from the amino acid tyrosine, others such as vasopressin and oxytocin, are short peptides, still other hormones, like insulin and glucagons, are longer polypeptide chains. Testosterone and estrogen are steroid hormones. Catecholamines, peptide and protein hormones are not lipid-soluble, and so, cannot enter their target cells through the bilipid layer of plasma membrane. Instead, these water-soluble hormones interact with a surface receptor, usually a glycoprotein, and thus, initiate a chain of events within it. The hormone insulin provides a well-studied example of how this happens.

Extracellular Receptor

The membrane bound receptors of insulin is a heterotetrameric protein consisting of four subunits, two -subunits protrude out from surface of the ell and bind insulin, and two -subunits that span the membrane and protrude into the cytoplasm.

Such receptors range from fewer than 100 in most cells in our body to more than 1,00,000 in some liver cells. Let us now consider the mechanisms whereby hormones induce their actions at the cellular and molecular levels.

1) Binding to the receptor

Binding of insulin to the outer subunits of the receptor causes a conformational change in the membrane spanning -subunits, which is also an enzyme, a tyrosine kinase. The activated -subunits add phosphate groups of specific tyrosine residues located in cytoplasmic domain of the receptor, as well as a variety of insulin receptor substrates.

2) Second messengers the mediator

As a result of -subunit activity, a transducer G protein activates enzyme phosphodiesterase. This enzyme makes phosphatidylinositol 4,5-biphosphate (PIP₂) into a pair of mediators inositoltriphosphate (IP₃) and diacylglycerol (DG). In turn, IP₃, which is water-soluble, and so diffuses into cytoplasm triggers the release of another messenger Ca²⁺ ions from intracellular endoplasmic reticulum activating many calcium-mediated processes. While DG remains in the membrane where it activates an enzyme called protein kinase C, which in turn, activates many other enzymes, such as pyruvate dehydrogenase, and so brings about the physiological effects.

3) Amplification of signal

Mediators amplify the signal in an expanding cascade of response. A single -subunit of insulin receptor, for example, activates many molecules of DG, and each protein kinase C molecule activated by DG will, in turn, activate many other enzyme molecules. DG and IP₃ are examples of second messengers, intermediary compounds that amplify a hormonal signal and so set into action a variety of events within the affected cell. A variety of events within the affected cell. A variety of hormones use another second messenger, the cyclic form of adenosine monophosphate, (cAMP). The enzyme adenylate cyclase converts adenosine triphosphate (ATP) into cAMP. Because an enzyme can be used over and over again, a single molecule of active adenylate cyclase can catalyse production of about 100 molecules of cAMP. In muscle or liver cells, when hormones, such as, adrenaline bind receptors, the receptors change shape and bind to G protein, causing it, in turn, to bind the nucleotide guanosine triphosphate (GTP) and activate another protein adenylate cyclase. The result of this complex cascade of interactions is the production of large amounts of cAMP.

cAMP activates the enzyme protein kinase A, which, in turn, activates the enzyme phosphorylate kinase. Each molecule of protein kinase A activates roughly 100 molecules of enzyme, phosphorylate kinase and so on. The net result is that a single molecule of adrenaline may lead to release of as many as 100 million molecules of glucose within only 1 or 2 minutes. No wonder only very small quantities of hormone are needed.

4) Antagonistic effect

Many cells use more than one second messenger. In heart cells, cAMP serves as a second messenger, speeding up muscle cell contraction in response to adrenaline, while cyclic guanosine monophosphate (cGMP) serves as another second messenger, slowing muscle contraction in response to acetylcholone. It is in this way that the sympathetic and parasympathetic nervous systems achieve antagonistic effect on heartbeat. Another example of antagonistic effect is insulin, which lowers blood sugar level, and glucagons, which raises it.

5) Synergistic effect

Another type of hormonal interaction is known as synergistic effect. Here, two or more hormones complement each others actions and both are needed for full expression of the hormone effects. For example, the production, secretion and ejection of milk by mammary glands require the synergistic effects of estrogens, progesterone, prolactin and oxytocin.

Intracellular Receptors

We have discussed many dramatic effects of hormone, for instance, testosterone. Yet, its concentration in the plasma of adult human male is only 30 to 100 ng per ml. How can hormones in such tiny quantities have such widespread and selective actions? Unlike catecholamine and peptide hormones, steroid and thyroid hormones are lipid-soluble hormones and readily pass through the plasma membrane of a target cell into the cytoplasm. There they bind to specific intracellular receptor proteins, forming a complex that enters the nucleus and bind to specific regulatory sites on chromosomes. The binding alters the pattern of gene expression, initiating the transcription of some genes (DNA), while repressing the transcription of others. This results in the production of specific mRNA translation products, proteins and usually enzymes. The actions of lipid-soluble hormones are slower and last longer than the actions of water-soluble hormones. These cause physiological responses that are characteristic of the steroid hormones.

http://www.youtube.com/watch?v=oOj04WsU9ko

Examples of peptide hormones

Hormones of hypothalamus (releasing and inhibitory factors), structure, mechanism of action.

Hypothalamus has the wide anatomic links with other parts of the brain. Therefore in different mental disorders there is the change of secretion of hypothalamus hormones.

http://www.youtube.com/watch?v=hLeBNyB1qKU&feature=related

Two groups of hormones are produced by hypothalamus corresponding to the anterior and posterior pituitary.

Hypothalamus and posterior pituitary. 3 peptides are synthesized in the hypothalamus that pass to the posterior pituitary along axons where they are accumulated: oxytocin, vasopressin (antidiuretic hormone) and neurophysin. The later binds the oxytocin and vasopressin and promotes their transportation to the pituitary.

Hypothalamus and anterior pituitary. Hypothalamus is connected with the anterior pituitary by the net of blood capillaries, so called hypothalamic portal system. Hypothalamus produces very active peptide compounds that pass via this portal system to anterior pituitary and stimulate or oppress the secretion of tropic hormones. Compounds stimulating the secretion are called releasing factors. 7 releasing factors are known according to the amount of tropic hormones of anterior pituitary:

- corticotropin-releasing factor

- thyrotropin-releasing factors

- somatotropin-releasing factors

- follicletropin-releasing factor

- luteotropin-releasing factor

- prolactotropin-releasing factor

- melanotropin-releasing factor.

Hypothalamus also secretes substances called inhibitory factors or statins, which can inhibit release of the some pituitary hormones. 3 inhibitory factors are known today:

- somatostatin

- prolactostatin

- melanostatin.

Releasing and inhibitory factors are produced in only minute amounts.

http://www.youtube.com/watch?v=-UaSfYKsFh0

Hormones of pituitury, structure, mechanism of action.

Tropic hormones are produced by the anterior pituitary. Usually tropic hormones not directly regulate the metabolism but act on the peripheral endocrine glands.

Somatotropic hormone (STH, growth hormone)

Chemical structure: simple protein

The intensity of secretion is regulated by the relationship between the somatotropic-releasing factor and somatostatin.

The main function of somatotropic hormone - stimulation of growth. Hormone is necessary for the bone tissue formation, for the muscle tissue growth, for the formation of peculiarities of men and women body.

Somatotropic hormone can act both directly on the metabolism and indirectly stimulating the synthesis of somatomedines (specific protein growth factors which are synthesized in liver).

The effect of somatotropic hormone on:

- protein metabolism: stimulates the passing of amino acids into the cells;

activates the synthesis of proteins, DNA, RNA.

- carbohydrate metabolism: activates the insulinase of liver;

inhibits the conversion of lipids to carbohydrates;

activates the exit of glucose from liver;

inhibits the entry of glucose into the cells.

- lipid metabolism: stimulates lipolisis;

stimulates the oxidation of fatty acids.

The deficiency of somatotropic hormone in children age causes nanism. Nanism - proportional underdevelopment of all body.

The deficiency of somatotropic hormone in adult persons hasn’t clinical symptoms. The excess of somatotropic hormone in children age causes gigantism.

The excess of somatotropic hormone in adult persons causes acromegalia (disproportional development of the separate body parts).

http://www.youtube.com/watch?v=VX2wgM4kUfM

Thyrotropic hormone (TTH).

Chemical structure: glicoprotein.

This hormone is necessary for the normal functions of thyroid glands.

Thyrotropic hormone promotes:

- accumulation of iodine in thyroid;

- including of iodine into the tyrosine;

- synthesis of thyroxine and triiodothyronine.

Adrenocorticotropic hormone (ACTH).

Chemical structure: polipeptide.

This hormone is necessary for the normal functions of adrenal cortex. It enhances the formation of steroid hormones and their secretion into the blood.

ACTH has also the melanocyte-stimulating activity.

Excessive secretion of ACTH causes the Icenko-Kushing disease (symptoms of hypercorticism, hyperpigmentation).

As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress.

The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol.

People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc.

Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne.

Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher.

One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease.

A patient with Cushing syndrome showing signs of acne and hirsuitism

Moon face in patienr with Cushing syndrome

Widened purple striae in a patient with Cushing's

Gonadotropic hormones.

Follicle stimulating hormone (FSH).

Chemical structure: glycoprotein.

Function: stimulates the function of follicles (oogenesis) in women and spermatogenesis in men.

FSH (follicle stimulating hormone) regulates the development, growth, pubertal maturation, and reproductive processes of the body
In both males and females, FSH stimulates the maturation of germ cells.
In males, FSH induces sertoli cells to secrete inhibin and stimulates the formation of sertoli-sertoli tight junctions (zonula occludens).
In females, FSH initiates follicular growth, specifically affecting granulosa cells. With the concomitant rise in inhibin B, FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that seems to be of importance to start the next ovulatory cycle.

Luteinizing hormone (LH).

Chemical structure: glycoprotein.

Function: stimulates the formation of yellow body in women and testosterone secretion in men.

In both males and females, (LH) Luteinising hormone is essential for reproduction.
In females, at the time of menstruation, FSH initiates follicular growth, specifically affecting granulosa cells. With the rise in estrogens, LH receptors are also expressed on the maturing follicle that produces an increasing amount of estradiol. Eventually at the time of the maturation of the follicle, the estrogen rise leads via the 48 hour period.

This 'LH surge' triggers ovulation thereby not only releasing the egg, but also initiating the conversion of the residual follicle into a corpus luteum that, in turn, produces progesterone to prepare the endometrium for a possible implantation. LH is necessary to maintain luteal function for the first two weeks. In case of a pregnancy luteal function will be further maintained by the action of hCG (a hormone very similar to LH) from the newly established pregnancy. LH supports thecal cells in the ovary that provide androgens and hormonal precursors for estradiol production.

In the male, LH acts upon the Leydig cells of the testis and is responsible for the production of testosterone, an androgen that exerts both endocrine activity and intratesticular activity on spermatogenesis.

Prolactin (PRL).

Chemical structure: protein.

Functions: - stimulates lactation;

- stimulates function of yellow body (secretion of progesterone);

- promotes formation of mother instinct;

- stimulates the formation of prostate glandular tissue in men.

Lipotropic hormone.

Chemical structure: protein.

Functions: - stimulates the mobilization of lipids from depot;

- decreases the Ca amount in blood;

- has the melanocyte-stimulating activity.

Melanocyte and melanin.

Posterior pituitary.

Vasopressin (Antidiuretic Hormone)

Chemical structure: peptide.

Functions: - activates the hyaluronidase. This enzyme splits the hyaluronic acid. The permeability of membranes is increased and reabsorption of water in kidneys is increased too. As result the day diuresis is decreased;

- narrows arterioles and capillaries and increases the blood pressure.

-

-

AVP has two principle sites of action: the kidney and blood vessels.

- The primary function of AVP in the body is to regulate extracellular fluid volume by affecting renal handling of water, although it is also a vasoconstrictor and pressor agent (hence, the name "vasopressin"). AVP acts on renal collecting ducts via V₂ receptors to increase water permeability (cAMP-dependent mechanism), which leads to decreased urine formation (hence, the antidiuretic action of "antidiuretic hormone"). This  increases blood volume, cardiac output and arterial pressure.

- A secondary function of AVP is vasoconstriction.  AVP binds to V₁ receptors on vascular smooth muscle to cause vasoconstriction via the IP₃ signal transduction pathway, which increases arterial pressure; however, the normal physiological concentrations of AVP are below its vasoactive range. Studies have shown, nevertheless, that in severe hypovolemic shock, when AVP release is very high, AVP does contribute to the compensatory increase in systemic vascular resistance.

The deficiency of vasopressin in organism causes diabetes insipidus. Clinical symptoms - poliuria, dehydration of the organism, low density of the urine.

Diabetes insipidus results in excessive thirst and urination. The reason is problems with a particular hormone or its receptor. Diabetes insipidus increases the risk for dehydration.

What Is Diabetes Insipidus?

Diabetes insipidus is caused by problems related to a hormone called antidiuretic hormone or its receptor. Antidiuretic hormone (ADH) is produced in a part of the brain called the hypothalamus. It's stored in the brain's pituitary gland. Release of ADH causes the kidneys to hold onto water, which makes urine more concentrated.

Normally, if we are thirsty or slightly dehydrated, ADH levels rise. The kidneys reabsorb more water and excrete concentrated urine. If, on the other hand, we chugged a half-gallon of water (don't try this at home), ADH levels would fall. Clear, dilute urine would pass. Diabetes insipidus can be caused by either of two problems with ADH. One is too little ADH is produced. When that's the case, the condition is called central diabetes insipidus. The other is there's enough ADH produced, but the kidneys can't respond to it. That condition is known as nephrogenic diabetes insipidus.

In either form of diabetes insipidus, the result is the same. The kidneys can't do their job of conserving water. Even when a person with diabetes insipidus is dehydrated, the kidneys will excrete abundant, dilute urine. This inability of the kidneys to conserve water leads to the symptoms of diabetes insipidus:

• Excessive thirst
• Excessive urine production (polyuria)

In some people, these symptoms can become extreme, causing dehydration.

Excessive fluid losses can also cause electrolyte imbalances. Possible symptoms include:

• Unexplained weakness
• Lethargy
• Muscle pains
• Irritability

But why "insipidus?" People with diabetes insipidus aren't insipid, but their urine is. Insipid can mean dull or lacking flavor. Believe it or not, doctors long ago would taste urine to detect illness. Unlike diabetes mellitus, which results in sweet tasting urine, diabetes insipidus creates watery, flavor-free urine.

Oxytocin.

Chemical structure: peptide.

Functions: stimulates the contraction of smooth muscles, especially the muscles of uterus and muscle fibres of alveoluses of mammas.

Oxytocin is used for delivery stimulation, for stop of bleeding after delivery, for stimulation of lactation.

Numerically the largest group of signaling substances, these arise by protein biosynthesis. The smallest peptide hormone, thyroliberin (362 Da), is a tripeptide. Proteohormones can reach masses of more than 20 kDa—e. g., thyrotropin (28 kDa). Similarities in the primary structures of many peptide hormones and proteohormones show that they are related to one another. They probably arose from common predecessors in the course of evolution. Thyroliberin (thyrotropin-releasing hormone, TRH) is one of the neurohormones of the hypothalamus. It stimulates pituitary gland cells to secrete thyrotropin (TSH). TRH consists of three amino acids, which are modified in characteristic ways.

Thyrotropin (thyroid-stimulating hormone, TSH) and the related hormones lutropin (luteinizing hormone, LH) and follitropin (follicle-stimulating hormone, FSH) originate in the adenohypophysis. They are all dimeric glycoproteins with masses of around 28 kDa. Thyrotropin stimulates the synthesis and secretion of thyroxin by the thyroid gland.

Hormones of pancreas, structure, mechanism of action

Insulin is produced and released by the B cells of the pancreas and is released when the glucose level rises. Insulin reduces the blood sugar level by promoting processes that consume glucose— e. g., glycolysis, glycogen synthesis, and conversion of glucose into fatty acids. By contrast, it inhibits gluconeogenesis and glycogen degradation. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.

Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. With the exception of the metabolic disorder diabetes mellitus and metabolic syndrome, insulin is provided within the body in a constant proportion to remove excess glucose from the blood, which otherwise would be toxic. When blood glucose levels fall below a certain level, the body begins to use stored sugar as an energy source through glycogenolysis, which breaks down the glycogen stored in the liver and muscles into glucose, which can then be utilized as an energy source. As a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). In addition, it has several other anabolic effects throughout the body.

When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally.^[2] Patients with type 2 diabetes are often insulin resistant and, because of such resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan.

The human insulin protein is composed of 51 amino acids, and has a molecular weight of 5808 Da. It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds.

http://www.youtube.com/watch?v=V1LjRi8Nvv4

http://www.youtube.com/watch?v=VLiTbb6MaEU&NR=1

http://www.youtube.com/watch?v=ZsTSoLhl3Y4&feature=related

http://www.youtube.com/watch?v=nBJN7DH83HA&feature=related

Glucagon, a peptide of 29 amino acids, is a product of the A cells of the pancreas. It is the antagonist of insulin and, like insulin, mainly influences carbohydrate and lipid metabolism. Its effects are each opposite to those of insulin. Glucagon mainly acts via the second messenger cAMP Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels.

Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (enteroglucagon).

Physiologic Effects of Glucagon

The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:

• Glucagon stimulates breakdown of glycogen stored in the liver. When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose.
• Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job.

Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells.

Control of Glucagon Secretion

Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose.

Two other conditions are known to trigger glucagon secretion:

• Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal: In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.
• Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose.

In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin.

Disease States

Diseases associated with excessively high or low secretion of glucagon are rare. Cancers of alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion. These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin lesions.

Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is considerable evidence that aberrant secretion of glucagon contributes to the metabolic derangements seen in this important disease. For example, many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is normally suppressed by elevated levels of blood glucose.

What is diabetes mellitus?

Diabetes is a disease of the pancreas, an organ behind your stomach that produces the hormone insulin. Insulin helps the body use food(glucose) for energy. When a person has diabetes, the pancreas either cannot produce enough insulin, or the body uses the insulin incorrectly, or both. Insulin works together with glucose in the bloodstream to help it enter the body’s cells to be burned for energy. If the insulin isn’t functioning properly, glucose cannot enter the cells. This causes glucose levels in the blood to rise, creating a condition of high blood sugar or hyperglycaemia which is the hallmark of diabetes, and leaving the cells without fuel. When blood glucose rises above a certain level, it spills over into the urine.

What are the common types of diabetes?

There are two common forms of diabetes: type 1 and type 2.

• Type 1(Insulin dependent): Type 1 diabetes occurs because the insulin-producing cells of the pancreas are damaged. In type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body’s cells for use as energy. People with type 1 diabetes must use insulin injections to control their blood glucose. Type 1 is the most common form of diabetes in people under age 20, but it can occur at any age. Ten percent of people with diabetes are diagnosed with type 1.

• Type 2(Non-insulin dependent): In type 2 diabetes, the pancreas makes insulin, but it either doesn’t produce enough insulin or the insulin does not work properly. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.

Generally, type 2 diabetes is more common in people over age 40 who are overweight. However, the increased prevalence of obesity has increased the number of people under age 40 who are diagnosed with type 2 diabetes. Nine out of 10 people with diabetes have type 2.

What causes Diabetes Mellitus?

The following factors may increase your chance of getting diabetes:

• Family history of diabetes or inherited tendency
• African-American, Hispanic or Native American race or ethnic background
• Obesity (being 20 percent or more over your desired body weight)
• Physical stress (such as surgery or illness)
• Use of certain medications
• Injury to pancreas (such as infection, tumor, surgery or accident)
• Autoimmune disease
• Hypertension
• Abnormal blood cholesterol or triglyceride levels
• Age (risk increases with age)
• Alcohol (risk increases with years of heavy alcohol use)
• Smoking
• Pregnancy (Pregnancy puts extra stress on a woman’s body which causes some women to develop diabetes. Blood sugar levels often return to normal after childbirth. Yet, women who develop diabetes during pregnancy have an increased chance of developing diabetes later in life.)

How is diabetes diagnosed?

The preferred method of diagnosing diabetes is the fasting blood sugar test (FBS). The FBS measures your blood glucose level after you have fasted (not eaten anything) for 10 to 12 hours.

Normal fasting blood glucose is between 70 and 100 mg/dl for people who do not have diabetes. The standard diagnosis of diabetes is made when:

• A patient has a fasting blood glucose level of 126 mg/dl or higher on two separate occasions; or
• A patient has a random blood glucose level of 200 mg/dl or greater and has common symptoms of diabetes, such as:
• – Increased thirst
• –Frequent urination
• –Increased hunger
• –Fatigue
  –Blurred vision
• –Weight loss
• On occasion, an oral glucose tolerance test may aid in the diagnosis of diabetes or an earlier abnormality that may become diabetes – called impaired glucose tolerance.

Other symptoms may include:

• Slow healing sores or cuts
• Itchy skin (usually in the vaginal or groin area); yeast infections
• Dry mouth

What are some of the long-term complications of diabetes?

Retinopathy (eye disease): All patients with diabetes should see an ophthalmologist (eye specialist) yearly for a dilated eye examination. Patients with known eye disease, symptoms of blurred vision in one eye or who have blind spots may need to see their ophthalmologist more frequently.

Nephropathy (kidney disease): Urine testing should be performed yearly. Regular blood pressure checks also are important because control of hypertension (high blood pressure) is essential in slowing kidney disease. Generally, blood pressure should be maintained less than 130/80 in adults. Persistent leg or feet swelling also may be a symptom of kidney disease and should be reported to your doctor.

Neuropathy (nerve disease): Numbness or tingling in your feet should be reported to your doctor at your regular visits. You should check your feet daily for redness, calluses, cracks or breakdown in skin tissue. If you notice these symptoms before scheduled visits, notify your doctor immediately.

Other long-term may complications include:

• Eye problems, such as glaucoma and cataracts
• Dental problems
• High blood pressure
• Heart disease

Because of the link between obesity and type 2 diabetes, you can do a great deal to reduce your chance of developing the disease by slimming down if you are overweight. This is especially true if diabetes runs in your family.

In fact, studies have shown that exercise and a healthy diet can prevent the development of type 2 diabetes in people with impaired glucose tolerance — a condition that often develops prior to full-blown type 2 diabetes. Medications have also been shown to provide similar benefit. Both diabetes drugs metformin and Precose have been shown to prevent the onset of type 2 diabetes in people with this pre-diabetes condition.
In someone who already has diabetes, exercise and a nutritionally balanced diet can greatly limit the effects of both types 1 and 2 diabetes on your body. In diabetics, stopping smoking is one of the best ways to help prevent the damaging effects of diabetes. If you smoke, quit; smoking dramatically increases the risk of heart disease, particularly for people with diabetes.

http://www.youtube.com/watch?v=FEsTIOIufiQ

Hormones of adrenal glands.

Adrenal glands consist of two parts: external - cortex, internal - medulla.

http://www.youtube.com/watch?v=06jbq3bxKE0&feature=related

Epinephrine is a hormone synthesized in the adrenal glands from tyrosine. Its release is subject to neuronal control.This “emergency hormone” mainly acts on the blood vessels, heart, andmetabolism. It constricts the blood vessels and thereby increases blood pressure; it increases cardiac function; it promotes the degradation of glycogen into glucose in the liver and muscles; and it dilates the bronchia.

Each part secrets specific hormones.

Hormones of adrenal medulla – catecholamines (epinephrine, norepinephrine, dopamine).

Chemical structure - these hormones are derivatives of amino acid tyrosine.

Epinephrine, norepinephrine, dopamine exist in blood in free state and connected with albumins, erythrocytes, glucuronic acid. Hormones undergo metabolism very fast (half time - some minutes).

Functions: causes very potent contraction of vessels and increase the blood pressure, increase a pulse rate. Epinephrine relaxes the smooth muscles of bronchi, intestine, promote the contraction of uterus smooth muscle. Epinephrine play a great role in stress reactions.

Catecholamine, any of various naturally occurring amines that function as neurotransmitters and hormones within the body. Catecholamines are characterized by a catechol group (a benzene ring with two hydroxyl groups) to which is attached an amine (nitrogen-containing) group. Among the catecholamines are dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

All catecholamines are synthesized from the amino acid l-tyrosine according to the following sequence: tyrosine → dopa (dihydroxyphenylalanine) → dopamine → norepinephrine (noradrenaline) → epinephrine (adrenaline). Catecholamines are synthesized in the brain, in the adrenal medulla, and by some sympathetic nerve fibres. The particular catecholamine that is synthesized by a nerve cell, or neuron, depends on which enzymes are present in that cell. For example, a neuron that has only the first two enzymes (tyrosine hydroxylase and dopa decarboxylase) used in the sequence will stop at the production of dopamine and is called a dopaminergic neuron (i.e., upon stimulation, it releases dopamine into the synapse). In the adrenal medulla the enzyme that catalyzes the transformation of norepinephrine to epinephrine is formed only in the presence of high local concentrations of glucocorticoids from the adjacent adrenal cortex; chromaffin cells in tissues outside the adrenal medulla are incapable of synthesizing epinephrine.

l-Dopa is well known for its role in the treatment of parkinsonism, but its biological importance lies in the fact that it is a precursor of dopamine, a neurotransmitter widely distributed in the central nervous system, including the basal ganglia of the brain (groups of nuclei within the cerebral hemispheres that collectively control muscle tone, inhibit movement, and control tremour). A deficiency of dopamine in these ganglia leads to parkinsonism, and this deficiency is at least partially alleviated by the administration of l-dopa.

Under ordinary circumstances, more epinephrine than norepinephrine is released from the adrenal medulla. In contrast, more norepinephrine is released from the sympathetic nervous system elsewhere in the body. In physiological terms, a major action of the hormones of the adrenal medulla and the sympathetic nervous system is to initiate a rapid, generalized fight-or-flight response. This response, which may be triggered by a fall in blood pressure or by pain, physical injury, abrupt emotional upset, or hypoglycemia, is characterized by an increased heart rate (tachycardia), anxiety, increased perspiration, tremour, and increased blood glucose concentrations (due to glycogenolysis, or breakdown of liver glycogen). These actions of catecholamines occur in concert with other neural or hormonal responses to stress, such as increases in adrenocorticotropic hormone (ACTH) and cortisol secretion.

Furthermore, the tissue responses to different catecholamines depend on the fact that there are two major types of adrenergic receptors (adrenoceptors) on the surface of target organs and tissues. The receptors are known as alpha-adrenergic and beta-adrenergic receptors, or alpha receptors and beta receptors, respectively. In general, activation of alpha-adrenergic receptors results in the constriction of blood vessels, contraction of uterine muscles, relaxation of intestinal muscles, and dilation of the pupils. Activation of beta-adrenergic receptors increases heart rate and stimulates cardiac contraction (thereby increasing cardiac output), dilates the bronchi (thereby increasing air flow into and out of the lungs), dilates the blood vessels, and relaxes the uterus. Drugs that block the activation of beta receptors (beta blockers), such as propranolol, are often given to patients with tachycardia, high blood pressure, or chest pain (angina pectoris). These drugs are contraindicated in patients with asthma because they worsen bronchial constriction.

Catecholamines play a key role in nutrient metabolism and the generation of body heat (thermogenesis). They stimulate not only oxygen consumption but also consumption of fuels, such as glucose and free fatty acids, thereby generating heat. They stimulate glycogenolysis and the breakdown of triglycerides, the stored form of fat, to free fatty acids (lipolysis). They also have a role in the regulation of secretion of multiple hormones. For example, dopamine inhibits prolactin secretion, norepinephrine stimulates gonadotropin-releasing hormone secretion, and epinephrine inhibits insulin secretion by the beta cells of the islets of Langerhans of the pancreas.

The effect of epinephrine on carbohydrate metabolism:

- activates the decomposition of glycogen in liver and muscles;

- activates the glycolysis, Krebs cycle and tissue respiration;

- causes the hyperglycemia.

The effect of epinephrine on protein metabolism:

- activates the protein decomposition.

The effect of epinephrine on lipid metabolism:

- activates the tissue lipase, mobilization of lipids and oxidation of fatty acids.

- Norepinephrine (NE) and epinephrine (E) are both sympathomimetic catecholamines that are synthesized in the adrenal medulla and terminals of sympathetic neurons. Along the metabolic pathway, NE is synthesized first -- and when an enzyme adds a methyl group, you have epinephrine. NE is the main catecholamine in peripheral tissue and sympathetic neurons. E is mostly made in the adrenal medulla.

-

http://www.youtube.com/watch?v=4g25d7_Afmc

Tissue hormones

Hormonoids (tissue hormones, histohormones) - organic trace substances produced by different cells of different tissues (not by specific glands) that regulate metabolism on the local level (some hormonoids are produced in the blood too (serotonin, acetylcholine).

In the organs, the hormones carry out physiological and biochemical regulatory functions. In contrast to endocrine hormones, tissue hormones are only active in the immediate vicinity of the cells that secrete them. The distinctions between hormones and other signaling substances (mediators, neurotransmitters, and growth factors) are fluid. Mediators is the term used for signaling substances that do not derive from special hormone- forming cells, but are formbymany cell types. Acetylcholine is a  neurotransmitter. What that does is it releases chemicals into the brain and plays a role in normal brain functions such as sleep. Also, it deals with attention, learning, and memory skills. The mechanisms that the transmitter controls was a mystery until now. Scientist now know that acetycholine deals with communication between neurons. Located in the prefrontal cortex. This is the formula for acetylcholine.

 When acetylcholine is released it binds to a specific reactor. Next it begins to start a molecule cascade. Which then triggers physiological alterations. Which deals with how prefrontal cortical neurons are “wired” together.  This explains how acethlcholine is released into the brain. This process may actually have an effect in the formation of new associative memories. Most of this information can be found in the artical on acetylchonline. The Professor of Cellular Neuroscience, Zafar Bashir was the one who demonstrated how electron stimulation of the prefrontal cortex leads to the release of acetylcholine. Then Dr. Douglas Caruana carried out another experiment. He also found that acetylchonline when released into the prefrontal cortex it helps you remember things. But when to much has been released those memories start to be forgotten.

Just like the article said in the Journal of Neuroscience. Acetylcholine is a neurotransmitter which plays key roles in sleep and other normal functions. This is basically what acetylcholine does before of course we found out that to much of it is dangerous.

Gastrin is released in response to certain stimuli. These include:

• stomach distension
• vagal stimulation (mediated by the neurocrine bombesin, or GRP in humans)
• the presence of partially digested proteins especially amino acids
• hypercalcemia

Gastrin release is inhibited by:

• The presence of acid (primarily the secreted HCl) in the stomach (a case of negative feedback).
• Somatostatin also inhibits the release of gastrin, along with secretin, GIP (gastroinhibitory peptide), VIP (vasoactive intestinal peptide), glucagon and calcitonin.

Function

The presence of gastrin stimulates parietal cells of the stomach to secrete hydrochloric acid (HCl)/gastric acid. This is done both directly on the parietal cell and indirectly via binding onto CCK2/gastrin receptors on ECL cells in the stomach, which then responds by releasing histamine, which in turn acts in a paracrine manner on parietal cells stimulating them to secrete H+ ions. This is the major stimulus for acid secretion by parietal cells.

Along with the above mentioned function, gastrin has been shown to have additional functions as well:

• Stimulates parietal cell maturation and fundal growth.
• Causes chief cells to secrete pepsinogen, the zymogen (inactive) form of the digestive enzyme pepsin.
• Increases antral muscle mobility and promotes stomach contractions.
• Strengthens antral contractions against the pylorus, and relaxes the pyloric sphincter, which stimulates gastric emptying.
• Plays a role in the relaxation of the ileocecal valve.^[8]
• Induces pancreatic secretions and gallbladder emptying.^[9]
• Impacts lower esophageal sphincter (LES) tone, causing it to contract.

Heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule; it consists of a variably-sulfated repeating disaccharide unit: The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA-GlcN

Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells; pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine intestine or bovine lung. Heparin allows the body's natural clot lysis mechanisms to work normally to break down clots that have already formed.

Heparin binds to the enzyme inhibitor antithrombin (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin.

The conformational change inAT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly-negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason heparin's activity against thrombin is size-dependent, the ternary complex requiring at least 18 saccharide units for efficient formation. In contrast anti factor Xa activity only requires the pentasaccharide binding site
This size difference has led to the development of low-molecular-weight heparins and more recently to fondaparinux as pharmaceutical anticoagulants. Low-molecular-weight heparins and fondaparinux target anti-factor Xa activity rather than anti-thrombin (IIa) activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index

Secretin hormone production is stimulated by acid chyme entering the duodenum. This hormone stimulates the pancreas to release bicarbonate to neutralize the acid.

Secretin is a hormone that both controls the environment in the duodenum by regulating secretions of the stomach and pancreas, and regulates water homeostasis throughout the body. It is produced in the S cells of the duodenum, which are located in the crypts of Lieberkühn. In humans, the secretin peptide is encoded by the SCT gene. Secretin was also the first hormone to be identified.

Secretin regulates the pH within the duodenum by inhibiting gastric acid secretion by the parietal cells of the stomach, and by stimulating bicarbonate production by the centroacinar cells and intercalated ducts of the pancreas.

In 2007, secretin was discovered to play a role in osmoregulation by acting on the hypothalamus, pituitary, and kidney.

Secretin increases watery bicarbonate solution from pancreatic and bile duct epithelium. Pancreatic centroacinar cells have secretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and converts ATP to cyclic AMP. Cyclic AMP acts as second messenger in intracellular signal transduction and leads to increase in release of watery carbonate. It is known to promote the normal growth and maintenance of the pancreas.

Secretin increases water and bicarbonate secretion from duodenal Brunner's glands to buffer the incoming protons of the acidic chyme. It also enhances the effects of cholecystokinin to induce the secretion of digestive enzymes and bile from pancreas and gallbladder, respectively.

It counteracts blood glucose concentration spikes by triggering increased insulin release from pancreas, following oral glucose intake.

Although secretin releases gastrin from gastrinomas, it inhibits gastrin release from the normal stomach. It reduces acid secretion from the stomach by inhibiting gastrin release from G cells. This helps neutralize the pH of the digestive products entering the duodenum from the stomach, as digestive enzymes from the pancreas (e.g., pancreatic amylase and pancreatic lipase) function optimally at slightly basic pH.

In addition, secretin stimulates pepsin secretion from chief cells, which can help break down proteins in food digestion. It stimulates release of glucagon, pancreatic polypeptide and somatostatin.

Histamine, an important mediator (local signaling substance) and neurotransmitter, is mainly stored in tissue mast cells and basophilic granulocytes in the blood. It is involved in inflammatory and allergic reactions. “Histamine liberators” such as tissue hormones, type E immunoglobulins (see p. 300), and drugs can release it. Histamine acts via various types of receptor. Binding to H1 receptors promotes contraction of smoothmuscle in the bronchia, and dilates the capillary vessels and increases their permeability. Via H2 receptors, histamine slows down the heart rate and promotes the formation of HCl in the gastric mucosa. In the brain, histamine acts as a neurotransmitter.

They have hormone-like effects in their immediate surroundings. Histamine and prostaglandins are important examples of these substances. Histamine is found in plant and animal tissue and is released from mast cells as part of an allergic reaction in humans. Release of histamine stimulates gastric secretion and causes dilation of capillaries, constriction of bronchial smooth muscle, and decreases blood pressure.

Histamines are released from mast cells as an allergic response to abnormal proteins found in the blood. The mast cells are found in connective tissue that contains numerous basophilic granules and releases substances such as heparin and histamine in response to injury or inflammation of body tissues.

How severe can histamine reactions be?

It has recently been discovered that histamines may play a much larger roll in human disease than once thought. In the past, histamine production was blamed on some very common allergic reactions such as hay fever, bee sting reactions, and anaphylactic shock.

In recent studies, histamine involvement in chronic inflammatory and degenerative diseases such as Lupus, Arthritis, Gulf War Syndrome, Fibromyalgia, Leaky Gut Syndrome, and some skin disorders like Psoriasis and obscure Rashes, has come to light as causes of chronic inflammatory responses to abnormal proteins in the blood of chronically ill patients!

Histamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the affected tissues. It is found in virtually all animal body cells.

Histamine forms colorless hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, ''N^π-H''-histamine and ''N^τ-H''-histamine.

Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pK_a around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pK_a ≈ 5.8) will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.

Once formed, histamine is either stored or rapidly inactivated. Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is the deficiency of this enzyme that triggers an allergic reaction as histamines pool in the synapses. Histamine is broken down by histamine-N-methyltransferase and diamine oxidase. Some forms of foodborne disease, so-called "food poisonings," are due to conversion of histidine into histamine in spoiled food, such as fish.

Serotonin is a neurotransmitter

= Neurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell - cell to cell communicators

= Serotonin is produced in the body from amino acids

= Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and does cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents

= Drugs may hinder the natural use/loss of serotonin but Drugs do not incease the supply of serotonin.

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.