1. ENDOCRINE SYSTEM Hormone Action

2. What are hormones?
Broadly speaking, a hormone is any compound produced by a cell, which by binding to its cognate receptor alters the metabolism of the cell bearing the hormone-receptor complex.

3. Hormones action on the cellular level begins with the association of the hormone with its specific receptor. Hormones vary according to the location of the receptors and the nature of the signal or the second messenger used to mediate hormonal action.
Generally polypeptide and protein hormones and catecholamines bind to receptors located in the plasma membrane, while both steroid and thyroid hormones interact with intracellular receptors. The hormones can be classified by their chemical composition, solubility, location of their receptors and the nature of the signals that mediate hormonal effects. According to the last two points, hormones can be classified into;

4. Hormones that bind to intracellular receptors; eg
Hormones that bind to intracellular receptors; eg. Thyroid hormones, mineralcorticoids, glucocorticoids, sex hormones, and retinoic acid.
Hormones that bind to cell surface receptors;
The second messenger is c- AMP; eg. Catecholamines (except  1 adrenergic), FSH, LH, PTH, TSH.
The second messenger is c- GMP; eg. Atrial nitriuretic factor(ANF).
The second messenger is calcium or phosphatidylinositols (or both); eg.  1 adrenergic catecholamines, acetylcholine, gastrin, ….etc.
The second messenger is a kinas or phosphates cascade; eg. insulin, insulin- like growth factors (IGF- I and IGF- II), prolactin and growth hormone.

5. For hormones of group I, they are lipophilic (water insoluble), they thus need a carrier protein in the plasma, they posses a longer half life, their intracellular receptors could be either cytosolic or nuclear, and the ligand- receptor complex is the second messenger.
On the other hand, hormones in group II are water soluble, have a shorter half life (minutes), and bind to the cell surface membrane and can not pass to the inside, but their action is mediated through an intermediary molecule called second messenger (The hormone by itself is the first messenger).

6. When a hormone of group I is carried till the cell surface membrane, it diffuses within the membrane by its lipophilic property, but ultimately binds to its specific, high affinity receptor whether in the nucleus or in the cytoplasm. The hormone-receptor complex undergoes a temperature and salt dependent “Activation reaction” that results in size , confirmation and surface-charge changes that enable the complex to bind to a specific region of the DNA called Hormone Response Element (HRE).
In this way the hormone-receptor complex activates or inactivates a specific gene in the DNA sequence resulting in gene transcription into a specific m- RNA synthesis that would leave to the cytoplasm and being translated into a specific protein which expresses the primary messenger( i.e. the hormone); eg. Calcitriol (1, 25 DHCC) enhances the synthesis of specific calcium-binding protein in the intestinal mucosal cells and thus promotes calcium absorption.

7. To be discarded

9. Group II (Peptide Hormones);
This group contains the vast majority of hormones. These are water soluble, they bind to receptors in the plasma membrane, but utilizes the following intracellular secondary messengers:
AMP
Cyclic AMP is a nucleotide that is derived from ATP through the activity of an enzyme “Adenyl-cyclase”. Binding of hormones that utilize this mechanism to their specific receptors will result in their activation or suppression of this enzyme and thus in either increased or decreased intracellular levels of C- AMP. However, this process of activation or suppression is also a tissue dependant process.
Adenyl- cyclse is present on the inner surface of the cell plasma membrane and it is regulated by at least 2 GTP- dependant proteins which are (Gs and Gi). When this enzyme is stimulated , it catalyzes the conversion of ATP into c- AMP in the presence of magnesium ions (Mg+2).

10. In eucharistic cells, 4 molecules of c-AMP bind to a specific “protein kinas” which is responsible for protein phosphorylation. This binding activates this protein kinas and the active protein kinas will utilize an ATP molecule in the presence of Mg+2 to convert proteins to phosphoproteins which would then exert their biological effects. Actions caused by hormones that increase c-AMP concentration can be terminated by phosphodiesterases. These hydrolytic enzymes insure a rapid turnover of the signal (c- AMP) and hence rapid termination of the biological process.

12. Role of Calcium in Hormonal Action:
Ionized calcium (Ca+2) is a well known regulator of several biological processes including muscle contraction, nerve conduction, clotting mechanism, enzyme activity, and hormonal action as a second messenger. Class II-c hormones enhance membrane permeability to calcium ions and thereby increase Ca+2 influx intracellular.
The calcium- dependant regulatory protein is now referred to as Calmodulin, which is similar in structure and function to the muscle protein Troponin- C . It has four binding sites to calcium. Once these sites become fully occupied, this will produce a profound conformational change in the calmodulin molecule.
This change will insure an activation process of calmodulin. Such activation is similar to binding of c- AMP to protein kinas and subsequent activation of the latter. Active calmodulin is particularly involved in regulating various kinases and enzymes of cyclic nucleotide generation and degradation eg. Private kinas, adenyl- cyclase, glycogen synthase and others.

14. Role of Phosphatidylinositols Metabolism in Calcium - Dependant Hormonal Action:
When the cell surface receptors are occupied by their specific hormones such as ADH, Acetylcholine or 1- cathecholamine they become potent activators for (Phospholipase- C) enzyme which is an enzyme in the plasma membrane of the target cell. Activation of phospholipase -C is accompanied by the effect of a unique (G- protein) which would together result in increased Ca+2 influx to the intracellular space on one hand, and to the hydrolysis of [ Phosphatidyl inositol biphosphate or PIP-2] into (diacyl glycerol) and (inositol troposphere or IP- 3).

15. Diacyl glycerol activates (protein kinas), a process which needs Ca+2 for activation. Active protein kinas will change proteins in the cell cytosole into phosphoproteins which will then exert their biological effects.
IP- 3 acts on the intracellular reservoir of calcium ions (ER and mitochondria) to release further calcium ions. In this way, the hydrolysis of phosphatidyl inositol molecules result in both activation of protein kinases and increase the concentration of intracellular Ca+2.

16. The high level of Ca+2 inside the cell combines calmodulin at its specific binding sites. The calcium- Calmodulin complex complex can activate both specific and multifunctional calmodulin kinases which then also phosphorylates different proteins.

17. Insulin and insulin like growth factor (Class II- D), in addition to other hormones like prolactin and growth hormone act through a cascade of kinases and phosphates. Specific receptors of these hormones contain [Intrinsic Tyrosin Kinase].
Activation of this enzyme leads to activation of a number of cytoplasmic protein tyrosin kinas which will phosphor late one or more of cytoplasmic peptide segments, which will then get the way to the nucleus and bind to specific region of DNA and activate transcription.