Mechanisms of hormone actions

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Presentation transcript:

Mechanisms of hormone actions Endocrine 412

Objectives Defining hormones and their classifications. Listing the general characteristics of hormones. Identifying factors determining the response of target cells to hormones. Describing the different mechanisms of action of hormones. Listing hormones that bind to cell surface receptors. Listing hormones that bind to intracellular receptors.

General characteristics of hormones are molecules that are produced by special cells (not by all cells of the body) are secreted directly to blood (with no ducts) are available in very low concentrations in blood are transported in blood to work in distant sites have systemic actions have specific receptors (either intra- or extra-cellular ) in target tissues have different special mechanisms of actions The sensitive radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods for assay have enabled accurate and specific measurements of hormones levels

Receptors of hormones Hormones are present in very low concentrations in extracellular fluids (e.g. blood) In order to initiate their biologic effects, target cells must recognize hormones by binding to specific receptors A target cell is defined by its ability to bind selectively a given hormone via a receptor Receptors have at least 2 DOMAINS: 1- Recognition domain: binds to the hormone 2- Coupling domain: couples hormone recognition to some intracellular function by generating a signal Generally, COUPLING occurs by two ways: 1- Polypeptide hormones, protein hormones & catecholamines binding of hormones to plasma membrane receptors (extracellular receptors). 2- Steroid & thyroid hormones interact with intracellular receptors, form complexes that generates a signal.

The concentration of hormone as seen by target cells is determined by three factors: 1-Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits  More than one hormone can affect a given cell type  Hormones can exert many different effects in one cell or in different cells

The concentration of hormone as seen by target cells is determined by three factors: (cont.) 2-Rate of delivery: An example of this effect is blood flow to a target organ or group of target cells – high blood flow delivers more hormone than low blood flow. 3-Rate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes. Hormones are cleared by: 1- Metabolic destruction by tissues 2- Binding with tissues 3- Excretion by the liver into bile 4- Excretion by the kidney into urine 5- Clearance of protein bound hormones is slower than clearance of peptide hormones

Classifications of hormones Hormones are classified according to: 1- Chemical composition (protein or others) 2- Solubility (hydrophilic or lipophilic) 3- Location of receptors (intra- or extra-cellular) 4- Nature of signal used to mediate hormone action within cells According to classifications 3 & 4, hormones are classified into Group I & Group II (according to mechanism of action)

Classification of hormones according to mechanism of action: Group I Hormones that bind to intracellular receptors (cytosolic or nucleus): 1- Solubility: lipophilic (to pass cell membrane which is mainly lipid) 2- Chemical composition: Derived from cholesterol (except: thyroid hormones & retinoic acid) 3- Transport in blood: Associate with transport proteins (to tackle solubility problem) Long plasma half-life 5-Mechanism of action: 1- Free hormone traverses plasma membrane of cells & binds to receptor in cytosol or nucleus of target cells. 2- Hormone-receptor complex binds to specific region in DNA of gene (hormone-response element, HRE) 3- Binding causes activation or inactivation of specific gene(s) transcription (production of mRNA) 4- Accordingly, amount of protein synthesis (production) is changed (protein may be enzymes of metabolic react.) 5- Accordingly, certain metabolic processes are affected. binding to proteins helps to Provide reservoirs Slow hormones clearance

Example of Group I hormones: Steroid hormones Cytosolic Receptors

Example of Group I hormones: Retinoic acid (active product of vitamin A) Nuclear Receptors

List of Group I hormones Thyroid hormones Steroid hormones: Glucocorticoids (e.g. cortisol hormone) Mineralocorticoids (e.g. aldesterone) Androgens (e.g. testosterone hormone) Estrogens Progestins (e.g. progesterone hormone) Retinoic acid (active metabolite of vitamin A) Calcitriol (1, 25 DHCC, active metabolite of vitamin D)

Classification of hormones according to mechanism of action: Group II Hormones that bind to plasma membrane (extra-cellular) receptors: 1- Solubility: hydrophilic 2- Chemical composition: Polypeptides, proteins, glycoproteins & catecholamines 3- Transport in blood: No transport protein- short plasma half-life 5-Mechanism of action: Hormone binds to plasma membrane receptor Hormone -receptor interaction leads to generation of second messenger intracellularly that communicates (couples) hormones binding with intracellular metabolic processes Second messengers: 1- cyclic AMP (cAMP) 2- cyclic GMP (cGMP) 3- Calcium or phosphaitdyl inosiltol (or both) 4- Kinase cascade

Second Messenger: cAMP

List of Group II hormones 1- Second messenger is cAMP: a2 & b adrenergic Catecholamines Adrenocorticotropic Hormone (ACTH) Angiotensin II Antidiuretic Hormone (ADH) Calcitonin Human Chorionic Gonadotropins (hCG) Corticotropin-releasing hormone (CRH) Follicle Stimulating Hormone (FSH) Leutinizing Hormone (LH) Glucagon Ipotropin (LPH) MSH (Melanocyte Stimulating Hormone) Parathyroid Hormone (PTH) Somatostatin Thyroid Stimulating Hormone (TSH)

List of Group II hormones 1- Second messenger is cGMP Atrial natriuretic peptide (ANP) Nitric Oxide (NO) There are two isoforms of guanylate cyclase involved in production of cGMP: A membrane-bound guanylate cyclase ( for ANP & bacterial endotoxin) A cytosolic guanylate cyclase (for NO) The binding of enterotoxin in plasma membrane of intestinal cells causes diarrhea with depression of water absorption from the intestine due to resulting altered transport of chloride and other ions

Second messenger cGMP: Atrial Natriuretic Peptide GC: Gunaylate cyclase

NO• signaling in physiology Nitric Oxide Synthase NO• Binds to heme moiety of guanylate cyclase Conformational change of the enzyme Increased activity (production of cGMP) Modulation of activity of other proteins (protein kinases, phospho- diesterases, ion channels) Physiological response (relaxation of smooth muscles, inhibition of platelet aggregation, etc.) O2-• ONOO-

Second Messenger: Phosphatidyl inositol & calcium

List of Group II hormones 1- Second messenger is phosphatidyl inositol or calcium (or both together) Acetylcholine a1 adrenergic catecholamines Angiotensin II Antideuretic Hormone (ADH) Cholecystokinin Gastrin Gonadotropin –Releasing Hormone (GnRH) Oxytocin Platelet Derived Growth Factor (PDGF) Substance P Thyrotropin Releasing Hormone (TRH)

Second Messenger: Kinase cascade (for insulin hormone) Binding of insulin on a-subunits Of insulin receptors Phosphorylation of b-subunits of insulin response substrates (IRS) CHANGE IN Gene Metabolism Growth Expression

List of Group II hormones 1- Second messenger is kinase cascade: Chorionic somatomammotropin (CS) Epidermal Growth factor (EGF) Erythropoeitin (EPO) Antideuretic Hormone (ADH) Fibroblast Growth Factors (FGF) Growth Hormone (GH) Insulin Insulin-like Growth factors (IGF-I & IGF-II) Nerve Growth Factor (NGF) Platelet Derived Growth Factor (PDGF) Prolactin (PRL)