mechanism of hormonal Action| types of hormones| function| structure|

    Mechanism of Hormonal Action    

The function of different hormones is to control the activity of level of target tissues. To achieve this, the hormones may alter either the permeability of the cells or they may activate some other specific cellular mechanism. Although the exact site of action of any hormone is not established, five general sites have been proposed: -

 (A.) Hormonal action at cyclic nucleotides level: -Many hormones exert their effect on cells in the first causing the formation of a substance, cyclic 3', 5'-adenosine monophosphate (Figure)in the cell. Once formed, the cycle AMP causes the hormonal effects inside the cell. Thus, cyclic AMP acts as intracellular hormonal mediator. It is also frequently referred to the second to messenger for hormone mediation; the first messenger being hormone the original hormone itself.

The effects of cyclic AMP on the action of a hormone were first described by Earl W. Sutherland and T.W. Rall in 1960. They found that the effect of epinephrine on hepatic glycogenolysis (breakdown of glycogen) is a result of the conversion of inactive phosphorylase by into an active form by cyclic AMP. Epinephrine was found to activate the enzyme, adenyl cyclase which, in turn, converts ATP to cAMP. Besides epinephrine, other hormones like glucagon, parathormone, ACTH, TSH, ICSH, LH, a-MSH and vasopressin are now known to have a stimulatory effect on cAMP levels. Several hormones, on the contrary, decrease cAMP levels and thus produce an opposite effect. These include insulin, melatonin and the prostaglandins. From the many names of hormones given above, it appears that hormone action not mediated by cAMP may be an exception rather than the rule. 

The following Figure depicts, in a schematic way, the effect of cAMP on hormone action. The stimulating hormone acts at the plasma membrane of the target cell and combines with a specific receptor for that particular type of hormone. The specificity of the receptor determines which hormone will affect the target cell. The combination of the hormone with its receptor leads to the activation of the enzyme, adenyl cyclase, which is also bound to the plasma membrane. The portion of the adenyl cyclase that is exposed to the cytoplasm causes 1mmediate conversion of cytoplasmic ATP into cAMP. The reaction representing cAMP synthesis may, thus, be written as: -

The reaction is slightly endergonic and has G°" value of about 1.6 kcal/mol. The then acts inside the cell to initiate a number destroyed. The various functions of cellular functions before it itself is initiated include: 

(a) activating the enzymes 

(b) altering the cell permeability 

(c) synthesizing the intracellular proteins 

(d) contracting or relaxing the muscles

(e) releasing other hormones (third messengers)

It should, however, be emphasized that what cAMP does in a particular affecter. cell is determined by the cell itself, rather than by cAMP. Cyclic AMP is however, destroyed (or inactivated) by a specific enzyme called phosphodiesterase, which hydrolyzes it to AMP. Like adenyl cyclase, the phosphodiesterase is present in practically all tissues.

This reaction is highly exergonic, having G°" value of about -12 kcal/mol. Cyclic. AMP is a very stable compound unless hydrolyzed by a specific phosphodiesterase. An important feature of the second messenger model is that the hormone need not enter the cell and its impact is made at the cell membrane. The biological effects of the hormone are mediated inside the cell by cAMP rather than by the hormone itself.

(B) Induction of enzyme synthesis at the nuclear level: - A second major mechanism by which the hormones, especially, the steroidal and thyroidal ones, act is to cause synthesis of proteins in the target cell. These proteins are presumably the enzymes which, in turn, activate other functions of the cells. The mechanism behind the steroidal hormones is depicted in other functions of the cells. The sequence of events is as follows: 

1). The steroidal hormone enters the cytoplasm of the target cell where it binds with a specific. high-affinity receptor protein.

Fig.: Mechanism of action of protein; [The dissimilar steroidal hormones: ST=steroid; R=specific receptor shapes of Rare intended to represent different conformations a

2). The receptor protein-hormone complex, so formed, then diffuses into (or is 2. transported into) the nucleus, where it reacts with the nuclear chromatin. 

3). Somewhere along this route, the receptor protein is structurally altered to form a smaller protein with. Low molecular weight, or else the steroid hormone is transferred to a second smaller protein.

4). The combination of the small protein and hormone is now the active factor that stimulates the specific genes to form messenger RNA (mRNA) in the nucleus. 

5). The mRNA diffuses into the cytoplasm where it accelerates the translation process at the ribosome to synthesize new proteins. It is, however, noteworthy that a direct chemical reaction of the hormone with DNA or RNA polynucleotide is not likely. Instead, the hormone must first combine with a specific receptor protein, and it is this combination that acts on DNA chromatin. It is possible that the chromatin proteins may influence hormonal activity by modifying the ability of the receptor complex to bind with DNA.

The thyroidal hormones act similarly to enhance RNA and enzyme synthesis but may do so by directly binding with the specific receptor proteins present in the nuclear chromatin. The receptors present in the cytoplasm are less effective in this regard.

(C). Stimulation of enzyme synthesis at ribosomal level: - In the case of some hormones, the activity is at the level of translation of information carried by the mRNA on the ribosomes to' the production of enzyme protein. For example, the ribosomes taken from animals, which have been given growth hormone, have a capacity for protein synthesis in the presence of normal mRNA.

(D). Direct activation at the enzyme level: -It has been experimentally observed that treatment of the intact animal (or of isolated tissue) with some hormones results in a change in enzyme behavior which is not related to de novo synthesis. The cell membrane is usually required for such activity. Henceforth, it is possible that activation of a membrane receptor might be an initial step in hormone action.

(E). Hormone action at the membrane level: - Many hormones appear to transport a variety of substances, including carbohydrates, amino acids and nucleotides, across cell membranes. These hormones, in fact, bind to cell membranes and cause rapid metabolic changes in the tissue. Catecholamines (epinephrine and norepinephrine) and many protein hormones stimulate different membrane enzyme systems by direct binding to specific receptors on cell membrane rather than in the cytoplasm.