1.04k likes | 1.07k Views
Hormones, Receptors, and Signal Transduction MCB 720 March 2, 2010. John J. Kopchick, Ph.D. Hormone -Receptor Interactions. Hormone stems from a Greek term meaning “ to spur on .”. General principles. Higher organisms, from the fruit fly to humans, are comprised of cells.
E N D
Hormones, Receptors, and Signal TransductionMCB 720March 2, 2010 John J. Kopchick, Ph.D.
Hormone -Receptor Interactions Hormonestems from a Greek term meaning“to spur on.”
General principles Higher organisms, from the fruit fly to humans, are comprised of cells. The cells often unite to form tissue which come together to form organs which together make up the organism. Cells of an organism do not live in isolation. Thecommunicationbetween cells ultimately controls growth, differentiation, and metabolic processes within the organism. Communication between cells is often by direct cell to cell contact. Communication frequently occurs between cells over short and long distances.
General principles cont... In cases of short and long distance communication, a substance may be released by one cell and recognized by a different targetcell. In the target cell, a specific response is induced. Cells use an amazing number of signaling chemicals. These signaling molecules are termed “hormones.” The ability of a hormone to induce a response in a target cell is usually mediated by a hormone receptor on, or in, the target cell.
General characteristicsof hormones Hormones are molecules synthesized by specific tissue. Classically these tissue were called glands. Hormones are secreted directly into the blood which carriesthem to their sites of action. Hormones are present at very low levels in the circulatory system. Hormones specifically affect or alter the activities of the responsive tissue (target tissue). Hormones act specifically via receptors located on, or in, target tissue.
Mediator Protein Hormone Receptor Effectors H1 R1 G1 E1 Range of possible pathways H2 R2 G2 E2 Possible pathways of transmission of hormonal signal. Each hormone can work through one or more receptors; each hormone-receptor complex can work through one or more mediatorproteins (either G proteins or other signaling mechanism), and each mediating protein or enzyme activated by hormone-receptor complexes can affect one or more effectorsfunctions.
Growth & Development Reproduction The four primary arenas of hormone action Hormones Maintenance of internal environment Energy production, utilization & storage
Definitions Endocrine- Refers to the internal secretion of biologically active substances. Exocrine - Refers to secretion outside the body, for example, through sweat glands, mammary glands, or ducts lead to the gastrointestinal. Hormone -Substances released by an endocrine gland and transported through the bloodstream to another tissue where it acts to regulate functions in the target tissue (classic definition). Paracrine- Hormones that act locally on cells that did not produce them. Autocrine- Hormones that act on cells that produced them. Receptors-Hormones bind to receptors molecules on cells. A receptor must specifically recognize the hormone from the numerous other molecules in the blood and transmit the hormone binding information into a cellular specific action.
Endocrine Blood vessel Hormone secretion into blood by endocrine gland Distant target cells Paracrine Secretory cell Adjacent target cell Autocrine Receptor Hormone or other extra cellular signal Target sites on same cell
Actions of hormones & neurotransmitters & their interrelationships (H,hormone; R, receptor; N,neurotransmitter.)
Hormone Source Principalfunctions Selected hormones & their functions Insulin Pancreas Controls blood-sugar level and storage of glycogen. Glucagon Pancreas Stimulates conversion of glycogen to glucose; raises blood sugar level. OxytocinPituitary gland Stimulates contraction of the uterine muscles and secretion of milk by the mammary glands. VasopressinPituitary gland Controls water excretion by the kidneys; stimulates contraction of the blood vessels. Growth hormonePituitary gland Stimulates growth. AdrenocorticotrophicPituitary gland Stimulates the adrenal cortex, which,in turn,releases hormone (ACTH) several steroid hormones. ProlactinPituitary gland Stimulates milk production by the mammary glands after birth of baby. EpinephrineAdrenal glands Stimulates rise in blood pressure, acceleration of heartbeat, decreased secretion of insulin, and increased blood sugar.
Hormone Source Principal functions Selected hormones & their functions cont... Cortisone Adrenal glands Helps control carbohydrate metabolism, salt and water balance, formation and storage of glycogen. Thyroxine &Thyroid gland Increases the metabolic rate of carbohydrates Triiodothyronine and proteins. CalcitoninThyroid gland Prevents the rise of calcium and phosphate in the body. Parathyroid Parathyroid gland Regulates the metabolism of calcium and phosphate in hormone in the body. GastrinStomach Stimulates secretion of gastric juice. Secretin Duodenum Stimulates secretion of pancreatic juice. Estrogen Ovaries Stimulates development and maintenance of female sexual characteristics. ProgesteroneOvaries Stimulates female sexual characteristics and maintains pregnancy. TestosteroneTestes Stimulates development and maintenance of male sexual characteristics.
Regulation of transcription by hormones that act on the cell surface.
Types of Hormones Catecholamines and Thyroid Hormones Small and derived from amino acids (epinephrine, thryoxine.) Steroid Hormones and Vitamin D Relatively small and derived from cholesterol Prostaglandin's Relatively small and derived from fatty acids Proteins or Polypeptides relatively large and derived from translation of hormone specific mRNA (growth hormone, insulin)
Thyroid Hormones Synthesized solely in the thyroidgland ( T4; 3’,5’,3,5-L-tetra-iodothyronine). Majority of the active form, T3 (3’,3,5-L-tri-iodothyronine), is produced in the peripheral tissues through deiodination of T4. Thyroid gland cells concentrates iodinefor thyroid hormone synthesis. Iodine is attached to tyrosine residues on a protein, termed thyroglobulin. Tyrosine residues are then coupled together to yield thyronines. Proteolytic digestion of thyroglobulin then yields T4 and T3 in a 10:1 ratio. Helps in the metabolism of sugars. The half life of T4 is 7 daysand that of T3 is 1 day.
Tyroxine [Tetra-iodothyronine (T4)] I I NH3+ O CH2 COO - CH HO Thyroid Hormones I I Tri-iodothyronine (T3) Increase of oxidation of sugars by most body cells; induction of some enzymes I I NH3+ HO O CH2 COO - CH I
T3 T4 T3 T3 T4 T3 T3 Regulation of transcription by thyroid hormones. T3 and T4 are tri-iodotyronine and tyroxine, respectively.
Steroid Hormones Produced in the adrenals, ovaries, testes, and placenta. Derived from cholesterol. Enzymes in the various glands control the final product. For example, cytochrome P450c11 which is located in the adrencortical cells, is involved in coritsolproduction. This enzyme is lacking in the gonads, that do not produce cortisol or aldosterone. Gonads, however, can produce dihydroxytestosterone, estradiol, or progesteronedepending upon the enzymes present in the gonadal tissue. Over 50 different steroid metabolites have been described.
Catecholamines Are synthesized in nervous tissues from which the adrenal medulla is derived. Adrenal medulla is the major source for circulating epinephrine. Synthesized from tyrosine which is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylases. Subsequent conversions to dopamine and then to nor epinephrine which is released by most catecholamine-producing cells of the body. In the adrenal medulla and a few other tissue, nor epinephrine is converted to epinephrine. The half life is 1-2 minutes. Flight, fright, or fight!
Prostaglandins and Leukotrienes They can be produced by most cells depending upon lipid and enzyme content of the cells. Arachidonic acid, which is derived from lipid metabolism, is the precursor compound. Depending upon the lipoxygenase present in the cell, either, HETE, prostaglandin (G2) or leukotrienes Cyclooxygenase(involved in PGG2 synthesis) is widely distributed throughout the body and is inhibited by aspirin, indomethacin, and other nonsteroidal and anti-inflammatory agents. The half-life is a few seconds. Several COX inhibitors!! - Problems
Tamoxifin Examples of hormone antagonists used in therapy Antagonist toUse Growth Hormone Acromegaly, Diabetes ProgesteroneContraceptive, abortion Glucocorticoid Spontaneous Cushing’s Syndrome Mineralo-corticoid Primary and secondary mineralocorticoid excess Androgen Prostate cancer EstrogenBreast cancer GnRH Prostate cancer -Adrenrgic Hypertension, hyperthyroidism Prostaglandin Acute and chronic inflammatory disease
Hormone Receptors Nuclear receptors estrogens Cytoplasmicreceptors Most steroid and thyroid hormones Cell surface membrane receptors Polypeptide hormones and catecholamines
A general model for the action of peptide hormones, catecholamines, and other membrane-active hormones. The hormone in the extra cellular fluid binds to the receptor and activates associated effector(s) systems, that may or may not be in the same molecule. This activation results in generation of an intracellular signal or second messenger that, through a variety of common and branched pathways, produces the final effectsof the hormone on metabolic enzyme activity, protein synthesis, or cellular growth and differentiation.
Amino acid Phosphorylation is very important in intracellular signal transduction ATP ATP S Serine Protein Kinases – transfer terminal Phosphate groups from ATP to Serine, Threonine, or Tyrosine residues in proteins Result in activation or inactivation of the recipient protein !
SSerine Threonine Y Tyrosine Amino acids that can be phosphorylated
Huising, et.al. J. Endo. 2006. 189:1-25
General View of Metabolism
Levels of blood sugar (glucose) regulate secretion of hormones from the pancreas Pancreas secretes insulin when glucose levels are high Insulin binds to insulin receptors on fat and muscle and “promotes” glucose uptake Overall effect: blood glucose levels return to normal