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Hormone Actions 2-May-17 Hormone actions 1 Hormone Receptors Hormones produce their effects by Combining with specific receptors The 1st step of hormone action Binding to receptor at the target cell Receptors can be located 1. 2. 3. 2-May-17 On target cell membrane In the cytoplasm In the nucleus Hormone actions 2 Hormone Receptors When hormone reacts with receptor Initiate a cascade of reactions in the cells With each stage becoming more powerful Thus even small conc of hormone 2-May-17 Can have a large effect Hormone actions 3 Hormone Receptors Hormone receptors Are large protein Each cell that is to be stimulated Has large number of receptors (2000 – 200,000) Each receptor (type) Highly specific for a single hormone Target tissue that are affected 2-May-17 Are those that have the receptor Hormone actions 4 Hormone Receptors i. Location of different type of hormone receptors In or on surface of cell membrane a. b. ii. Protein & peptide hormone Catecholamine In the cell cytoplasm 2-May-17 Steroid hormone Hormone actions 5 Hormone Receptors iii. In the nucleus 2-May-17 Thyroid hormones Hormone actions 6 Regulation of Numbers of Receptor Number of receptor in target cell Does not remain constant Receptor protein can be 1. 2. 2-May-17 Destroyed or inactivated Activated or new proteins can be formed Hormone actions 7 Regulation of Numbers of Receptor In most cases, the binding of hormone to receptor on target cell Number of active receptors 1. 2. This is known as “down-regulation” 2-May-17 Due to inactivation or Production of new receptors Cause in responsiveness of target tissue to the hormone Hormone actions 8 Regulation of Numbers of Receptor However, some hormone Can cause “up-regulation” of receptors Stimulating hormone Induces formation of new receptor The target tissue becomes progressively 2-May-17 Protein synthesis on target tissue More sensitive to the stimulating hormone Hormone actions 9 A. Intracellular Signaling Generally Binding of hormone to receptor Hormone – receptor complex Alter the function of receptor Activated receptor 2-May-17 Initiate the hormone effect Hormone actions 10 Intracellular Signaling 1. Change in membrane permeability Neurotransmitter substance Acetylcholine, nor epinephrine Combine with receptors on post synaptic membrane Change the structure of receptor Open or close ionic channels Movement of ions Subsequent effect on post synaptic cell 2-May-17 Hormone actions 11 Intracellular Signaling Circulating hormones Nor epinephrine & epinephrine Have similar effect of 2-May-17 Opening or closing ionic channels Hormone actions 12 Intracellular Signaling 2. Activation of intracellular enzymes Hormone receptor complex Activate or inactivate enzymes 2-May-17 Immediately inside the cell membrane Hormone actions 13 Intracellular Signaling Insulin Bind to receptor portion that protrudes outside the membrane Cause structural change in receptor molecule Causes the portion of receptor that protrude inside the cell To become activated kinase Promote phosphorylation of different substances 2-May-17 Hormone actions 14 Mechanism of Action of Insulin Insulin Glucose S S S S Tyrosine kinase Glucose Protein synthesis fat synthesis glucose synthesis growth & gene expression Phosphorylase enzyme Glucose transporters 2-May-17 Hormone actions 15 B. Second Messenger Some hormone Cannot penetrate cell membrane easily Interact with receptor on the exterior Coupling of receptor to intracellular enzyme machinery 2-May-17 Results in generation of an intracellular signal or message Known as “second messenger” Hormone actions 16 1.Cyclic AMP Second Messenger Hormone Receptor Adenyl cyclase Gs protein ATP cAMP Prot. Kinase-A Phosphorylated Prot. Hormone bind to receptor on cell surface Hormone – receptor complex Biological effect 2-May-17 Hormone actions Activate Gs protein Gs protein activates adenyl cyclase enzyme 17 Cyclic AMP Second Messenger Hormone Receptor Adenyl cyclase Gs protein Activated adenyl cyclase ATP cAMP Prot. Kinase-A Phosphorylated Prot. Biological effect 2-May-17 Catalyze the conversion of ATP cAMP cAMP activate protein kinase-A which Hormone actions Catalyzes the phosphorylation of proteins 18 Cyclic AMP Second Messenger Hormone Receptor Adenyl cyclase Gs protein The phosphorylated proteins ATP Produce the various physiologic effects cAMP Prot. Kinase-A Phosphorylated Prot. Biological effect 2-May-17 Hormone actions 19 2.Phospholipase-C Second Messenger Hormone Phospholipase-C Receptor PIP2 PLC Hormone bind to receptor DAG Gs protein Prot kinase-C IP3 Endoplasmic reticulum Phosphorylated prot Ca++ Cell response 2-May-17 Physiologic effect Hormone actions Hormone-receptor complex Activate G protein The G protein activate phospholipase-C (PLC) 20 Phospholipase-C Second Messenger Hormone Phospholipase-C Receptor PIP2 PLC The phospholipase-C (PLC) DAG Gs protein Prot kinase-C Catalyze breakdown of phospholipids in cell membrane IP3 Endoplasmic reticulum Phosphorylated prot Ca++ Cell response 2-May-17 Physiologic effect Hormone actions 21 Phospholipase-C Second Messenger Hormone Phospholipase-C Receptor PIP2 PLC DAG Phosphatidylinositol biphosphate (PIP2) converted into Gs protein Prot kinase-C IP3 Endoplasmic reticulum Phosphorylated prot Inositol triphosphate (IP3) and Diacylglycerol (DAG) Ca++ Cell response 2-May-17 Physiologic effect Hormone actions 22 Phospholipase-C Second Messenger Hormone Phospholipase-C Receptor Inositol triphosphate (IP3) PIP2 PLC DAG Gs protein Prot kinase-C IP3 Endoplasmic reticulum Phosphorylated prot Ca++ Cell response 2-May-17 Physiologic effect Hormone actions Mobilize Ca++ from endoplasmic reticulum (ER) intracellular Ca++ conc Cell response Diacylglycerol (DAG) 23 Phospholipase-C Second Messenger Hormone Phospholipase-C Receptor Diacylglycerol (DAG) PIP2 PLC DAG Gs protein Prot kinase-C IP3 Endoplasmic reticulum Phosphorylated prot Ca++ Cell response 2-May-17 Activate protein kinase-C (PKC) which Phosphorylates large number of protein Leading to cell response Physiologic effect Hormone actions 24 3.Ca++ - Calmodulin Second Messenger Ca++ Ca++ channel Ca++ entry into the cell by conc Ca++ Ca++ Ca++ Calmodulin complex Hormone actions Open Ca++ channels Hormone interact with membrane receptor Initiates physiologic effect 2-May-17 Change in membrane membrane pot Open Ca++ channels 25 Ca++ - Calmodulin Second Messenger Ca++ Ca++ channel On entering the cell conc Ca++ Ca++ Ca++ Calmodulin complex Ca++ bind to calmodulin The Ca++ calmodulin complex Activate calmodulin – dependent - kinases Initiates physiologic effect 2-May-17 Hormone actions Initiate multiple effects 26 Regulation of Gene Expression Hormone H-R complex H-R complex Hormone cause protein synthesis in target cells Protein then act as R Ribosome DNA mRNA Enzymes Transport proteins Structural proteins prot synthesis Nucleus Response 2-May-17 Hormone actions 27 Regulation of Gene Expression Hormone H-R complex H-R complex Hormones that act by this mechanism include R Ribosome DNA mRNA prot synthesis Steroids Thyroid hormones 1,25 dihydrocholecalcife rol Nucleus Response 2-May-17 Hormone actions 28 Regulation of Gene Expression Hormone H-R complex H-R complex R Ribosome DNA Hormone enter cytoplasm where either Bind to specific receptor mRNA prot synthesis Transformation of receptor Nucleus Expose DNA binding domain Response 2-May-17 Hormone actions 29 Regulation of Gene Expression Hormone H-R complex Receptor-hormone complex H-R complex Or some hormones R Ribosome DNA mRNA prot synthesis Nucleus Moves to DNA Enter cytoplasm and into the nucleus Then bind to receptor found in the nucleus Response 2-May-17 Hormone actions 30 Regulation of Gene Expression Hormone H-R complex To form Receptorhormone complex H-R complex R Ribosome DNA mRNA prot synthesis The binding of receptor-hormone complex to DNA Nucleus Which moves to DNA transcription of mRNAs Response 2-May-17 Hormone actions 31 Regulation of Gene Expression Hormone H-R complex H-R complex mRNAs are then translated in ribosomes R Ribosome DNA Production of protein Alters cell function mRNA prot synthesis Nucleus Response 2-May-17 Hormone actions 32 Regulation of Gene Expression Hormone H-R complex H-R complex R Ribosome DNA prot synthesis Nucleus Response Hormone actions Bind hormone in the nucleus Glucocorticoids receprors mRNA 2-May-17 Estrogen, triiodothyronine receptors Located in cytoplasm But migrate into nucleus as soon as it binds to hormone 33