Endocrinology

1. Endocrinology Endocrinology is concerned with the study of the biosynthesis, storage, chemistry, and physiological function of hormones and with the cells of the endocrine glands and tissues that secrete them.

2. Hormones • Hormones are the chemical messengers of the body. They are defined as organic substances secreted into blood stream to control the metabolic and biological activities. • These hormones are involved in transmission of information from one tissue to another and from cell to cell. These substances are produced in small amounts by various endocrine (ductless) glands in the body.

3. They are delivered directly to the blood in minute quantities and are carried by the blood to various target organs where these exert physiological effect and control metabolic activities. Thus frequently their site of action is away from their origin. Hormones are required in trace amounts and are highly specific in their functions. • The deficiency of any hormones leads to a particular disease, which can be cured by administration of that hormone.

5. The similarities and differences of hormone with enzyme. • Hormones act as body catalysts resembling enzymes, like enzymes they are required in small quantities,and they are not used up during the reaction. • While they are differ with enzymes: • 1-They are usually produced in an organ other than that in which they ultimately perform their action. • 2-They are usually secreted in blood prior to use. • 3-Structurally, they are not always proteins.

7. Endocrine action:- The hormone is distributed in blood and binds to distant target cells.Paracrine action:-The hormone acts locally by diffusing from its source to target cells in the neighborhood.Autocrine action:- The hormone acts on the same cell that produced it.

9. Target tissue:-For a given hormone is a tissue contains specific receptor proteins that bind the hormone and initiate a cellular response • Receptors :-Are specific molecules within the cell membrane , cytoplasm or nucleus of the target cell that are necessary for recognition and binding of extra cellular messenger (hormone) Target tissue must have two characters in responce to the hormone • 1-The tissue should recognize the hormone by a receptor. • 2-The tissue should have intracellular capacity of translating the massage of the hormone to biochemical event or reaction.

10. Regulation of target tissue activity.The hormones regulate the activities of their target tissues in two ways:-1-By regulating the activities of already present proteins in the cells, this takes place rapidly within minutes.2-By regulating the synthesis or degradation of proteins, taking place more slowly requiring hours or days.

11. Hormones as a signal • Hormonal signaling involves the following: • 1-Biosynthesis of a particular hormone in a particular tissue. • 2-Storage and secretion of the hormone. • 3-Transport of the hormone to the target cell(s). • 4-Recognition of the hormone by an associated cell membrane or intracellularreceptor protein. • 5-Relay and amplification of the received hormonal signal via a signal transduction process: This then leads to a cellular response. The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostaticnegative feedback loop. • 6-Degradation of the hormone.

13. Interactions with receptors • Hormone-receptor complex concentrations are effectively determined by three factors: • 1-The number of hormone molecules available for complex formation. • 2-The number of receptor molecules available for complex formation. • 3-The binding affinity between hormone and receptor

16. Characteristics of Receptors

21. Classification according to the mechanism of action • There are 2 groups:- • Group I :- includes H. that bind the intracellular receptors • Group II: - includes H. that bind to cell surface receptors.

23. Mechanism of actionGroup I (H.that bind to intracellular receptors)

24. Mechanism of action of group II (Hormone that bind to cell surface receptor)

28. Clinical Significance of G-Protein

29. The factors that regulate hormone action • Action of a hormone at a target organ regulated by four factors: _ 1-Rate of synthesis and secretion of hormone. 2-Specific transport systems in plasma. 3- Hormone-specific receptors in target cell membrane which differ from tissue to Tissue. 4-Ultimate degradation of the hormone usually by the liver or kidneys.

30. Hormonal Regulation • The ability of a cell to respond to a hormone depends on two properties of the receptor molecule: • 1- How many of them are on a particular cell. • 2- How well they bind the hormone. • The first property is called the receptor number, and the second is called the affinity of the receptor for the hormone. The biochemical responsiveness of a cell to a hormone

31. Hormones Receptor Interaction • Hormone + receptor  hormone – receptor complex • This complex usually undergoes conformational changes resulting from interaction with the hormonal ligand. These changes allow for a subsequent interaction with a transducing protein (G-protein) in the membrane or for activation to a new state in which active domains become available on the surface of the receptor.

32. Activation of Adenylate cyclase • Adenylate cyclase is a membrane-bound enzyme that is found in the plasma membranes of most mammalian cells. The system works as follows:- • Hormone binds to the membrane receptor protein (R). • This binding produce a conformational change which allows the bound GDP to exchange for GTP. As long as the site contains GTP, adenylate cyclase will be activated. • When GTP is hydrolysed by the GTP ase activity of the guanine nucleotide binding protein leaving GDP on the binding site, activation is reversed. • The enzyme can only be activated by the addition of hormone together with GTP or analogue of GTP.

33. Action of cAMP in cells. • Kinase is a tetramer made up of two types of subunit: - two regulatory and two catalytic subunits (C). Each R contains two binding sites for cAMP . • The liberated catalytic subunits ( C ) are able to phosphorylate proteins to produce a cellular effect of specific enzymes. • The enzymes may be either activated or inhibited by phosphorytation. • cAMP is inactivated by phosphodiesterase, which catalyze the conversion of cAMP to AMP. • The activity of phosphodiesterase may also be regulated by hormone. • Adenylate cyclase phosphodiestrase • ATP ------------------------- cAMP ------------------------ AMP + Pi

34. Phosphatidylinositol or Calcium Second Messenger • Certain hormone receptor interaction result in the activation of the enzyme phospholipase C attached to the inside projections of the receptors. The receptor binding and activation of phospholipase C are coupled by a specific G – protein • Certain hormones enhance membrane permeability to Ca² influx, this is probably accomplished by:- • Na +1 - Ca +² exchange mechanism. • Ca +²– 2H ATP ase – dependent pump..

36. Calcium Calmodulin Second Messenger • It is the calcium – dependent regulatory protein, which is homologous to the muscle protein troponin C in structure and function. • It has four Ca +² binding sites, and full occupancy of these sites leads to a marked conformational change. • This conformational change is presumably linked to calmodulins ability to activate or inactivate enzymes.

38. The hypothetical sequence of interactions between Ca +², calmodulin and target enzyme as follows:- • Calomdulin binds 2Ca +² at the high- affinity sites. • Conformational chang in calmodulin • Calmodulin / 2Ca +² complex binds to target enzyme • Conformational change in enzyme. • Second change in calmodulin conformation consequent upon change in enzyme conformation increase in Ca +² affinity of site 3 and 4. • Association of 2 further Ca +².