Mechanism of action of hormones acting on cell surface By Dr. Umar M.T

OUTLINE Introduction Hormones that act on cell membrane receptors Structure of cell membrane receptors Types of cell membrane receptors Mechanisms of action Clinical relevance Conclusion

Introduction Hormones can be defined as chemical signals secreted into the blood stream that act on distant tissues, usually in regulatory fashion To respond to a hormone, a target cell must contain the essential components of a signaling pathway Hormone binds to receptor resulting in an appropriate downstream signaling pathways that leads to physiologic responses

Hormones that act on cell membrane receptors They include polypeptide hormones, monoamines and Prostaglandins They hydrophilic in nature Can not cross cell membrane As such need a 2 nd messenger to carry out their effect inside cell Examples Insulin GH Catecholamines Prolactin etc

Structure of cell membrane receptors Cell surface receptors are integral membrane proteins They have three regions/domains 1.Extracellular domain 2.Transmembrane domain 3.Intracellular domain

Structure of cell membrane receptors cont’d Extracellular domains: Hydrophilic Ligand binding domain Locate outside cell surface Binds to 1 st messenger/hormone Transmembrane domains: Located within cell membrane Hydrophobic Anchors the receptor

Structure of cell membrane receptors cont’d Intracellular domains: Cytoplasmic domain Tail of receptor Interacts with molecules leading to generation of second messenger

Membrane receptor types 1.Single pass protein receptor e.g Growth factor receptor 2.Multiple subunits receptor e.g Insulin receptor 3.Serpentine receptor e.g Adrenergic receptor

Membrane receptor types cont’d

Receptor-couple activity Ion channel- linked receptor Enzyme linked receptor G-protein- couple recptor

Mechanisms of action Signal transduction. Binding of hormone (1 st messenger) to receptor initiates a series of events This leads to generation of 2 nd messengers within the cell The second messengers then trigger a series of molecular interactions that alter the physiologic state of the cell. 1 st messenger→ Receptor→ 2 nd messenger→ Physiologic effect

2 nd messengers & associated hormones Second MessengerExamples of Hormones Which Utilize This System Cyclic AMP Catecholamine, Glucagon, LH, FSH, TSH, Calcitonin, PTH, ADH Protein kinase activity Insulin, GH, Prolactin, Oxytocin, Erythropoietin, Growth factors Calcium and/or phosphoinositides Catecholamine, Angiotensin II, ADH, GnRH, TSH. Cyclic GMP ANP, NO

Cyclic AMP Second Messenger Systems Hormone binds to receptor through a set of G proteins which activate adenylate cyclase in the cell membrane. Activated adenylate cyclase convert ATP to cAMP, resulting in ↑cAMP ↑cAMP in the cytosol activate protein kinase A Activated protein kinase A phosphorilate to other enzymes leading to physiologic activity The process is deactivated by Phosphodiesterase which↓ cAMP

Tyrosine Kinase Second Messenger Systems The hormone binds to receptor domains exposed on the cell surface Resulting in a conformational change leading to auto phosphorylation of the receptor The activated receptor phosphorylates a variety of intracellular enzymes leading to physiologic events.

Insulin receptor

Calcium ion channels messenger systems

Clinical relevance 1.Some receptor defects are associated with endocrine disorders 2. Some medications act via cell receptors 3. Some cancers are associated with receptors that continually stimulate second messengers

Diseases Caused by G Protein–Coupled Mutations Familial male precocious puberty Familial non-autoimmune hyperthyroidism Familial hypocalcemic hypercalciuria Nephrogenic DI Familial ACTH resistance Familial GH deficiency Hypogonadotropic hypogonadism

Conclusion Understanding the mechanism of hormone action is very important in treating some medical disorders It encompasses knowing the structure and function of a receptor How the hormone bind to receptor and transduces a signal to effectors inside cells.

THANKS NAGODE