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BIOCHEMISTRY MEDICAL FACULTY USU Intercelluler Communication All cells detect and respond to environmental stimuli Intracelluler communication : - endocrine - nervous - immune Endocrine glands secrete hormones BIOCHEMISTRY MEDICAL FACULTY USU Long Distance Communication: Hormones Signal Chemicals Made in endocrine cells Transported via blood Receptors on target cells Long distance cell-to-cell communication BIOCHEMISTRY MEDICAL FACULTY USU Paracrines and Autocrines Local communication Signal chemicals diffuse to target Example: Cytokines – Autocrine– Autocrine–receptor on same cell – Paracrine Paracrine–– neighboring cells BIOCHEMISTRY MEDICAL FACULTY USU Direct and local cell-to-cell communication Signal Pathways Signal molecule (ligand) Receptor Intracellular signal Target protein Response BIOCHEMISTRY MEDICAL FACULTY USU Signal pathways Hormone Receptors Receptors : a protein that binds a hormone with high affinity All receptors are proteins Have at least two functional domains : 1. A recognition domain binds the hormone ligand 2. A second region generates a signal that couples hormone recognition to some intracellular function BIOCHEMISTRY MEDICAL FACULTY USU Hormone Receptors Only the target cells for a certain hormone have receptors for that hormone Receptor density of target cells: – 2000 2000--100,000 receptors/hormone BIOCHEMISTRY MEDICAL FACULTY USU Receptor locations Cytosolic or Nuclear – Lipophilic ligand enters cell – Often activates gene – Slower response Cell membrane – Lipophobic ligand can't enter cell – Outer surface receptor – Fast response BIOCHEMISTRY MEDICAL FACULTY USU Hormone - Target Cell Specificity Receptors are dynamic structures: they can respond to rising levels of hormones by increasing in number (up up--regulation regulation)) Respond to prolonged exposure to high hormone concentrations by reducing the number of receptors (down (down-regulation)) regulation BIOCHEMISTRY MEDICAL FACULTY USU Receptors Intracelluler Hormones can diffuse through the lipid bilayer of the plasma membrane receptors intracelluler The lipid soluble hormone diffuses into the cell Binds to the receptor conformational change Binds to specific DNA sequences response elements (HRE) BIOCHEMISTRY MEDICAL FACULTY USU Receptors Intracelluler These DNA sequences are in the regulatory regions of genes. Stimulating the transcription of messenger RNA. The messenger RNA travels to the cytoplasm translated into protein BIOCHEMISTRY MEDICAL FACULTY USU Mechanism of lipid soluble hormone action BIOCHEMISTRY MEDICAL FACULTY USU Action of Steroid Hormones BIOCHEMISTRY MEDICAL FACULTY USU Receptors on The Plasma Membrane Receptors for the water soluble hormones Couple to various second messenger systems mediate the action of the hormone in the target cell Second messenger : cAMP cGMP Ca 2+ Phosphoinositide/Diacylglycerol(DAG) Protein Kinase Membrane-bound Hormone Receptors Second Messenger Systems 1.Cyclic 1. Cyclic AMP (cAMP) Polypeptide or glycoprotein hormones bind to receptor protein dissociation of a subunit of GG-protein The GG-protein is trimer ( (, and subunit) The subunit: - bound to GDP in the native G protein BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 1. Cyclic AMP (cAMP) - the hormone receptor complex exchange of GTP - dissociates from G - stimulates the adenylate cyclase - ATP is converted to cAMP ATP cAMP + PPi BIOCHEMISTRY MEDICAL FACULTY USU Activation of adenylate cyclase by binding of a hormone to its receptor Second Messenger Systems 1. Cyclic AMP (cAMP) - The generation of cAMP usually activates protein kinase A (PKA) - This results in activation of cAMPdependent protein kinase (PKA) with consequent Activation of PKA phosphorylation of target proteins BIOCHEMISTRY MEDICAL FACULTY USU 1. Cyclic AMP (cAMP) - cAMP hydrolyzed by cAMP phosphodiesterase to 55-AMP - phosphodiesterase inhibited by methylxanthine derivatives BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 1. Cyclic AMP (cAMP) Cholera toxin -block Gs, hydrolysis of GTP to GDP -severe diarrhea Pertussis toxin -block Gi, exchanging GDP for GTP -whooping cough Cholera toxin Pertussis toxin Action of Vasopressin/VP in Distal Kidney Tubules Second Messenger Systems 2. Cyclic GMP (cGMP) Membrane bound Guanylate cyclase is an integral part of the receptor and hence is structurally similar to tyrosine specific protein kinases GTP Guanylate cyclase cGMP Protein kinase G BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 2. Cyclic GMP (CGMP) Atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) activate guanylate cyclase Increase blood volume : release ANF from heart atrial cells. Effects : lowering of BP via vasodilation and diuresis ANF cGMP increase renal excretion of Na+ and water BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 2. Cyclic GMP (CGMP) Nitric oxide (NO): stimulate synthesis of cGMP The resultant rise in cGMP muscle relaxation, through activation of PKG, which phosphorylates myosin lightlightchain kinase and renders it inactive used to treat patients with angina BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 3. Calcium Many cells respond to extracellular stimuli by altering their intracellular calcium concentration concentration interaction with calmodulin Calcium levels controlled by phosphoinositide system Calcium ion may be more of a third messenger BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems 4. Phosphoinositide Phosphoinositide/ /Diacylglycerol (DAG) Cytosolic calcium ion levels increased by release from intracellular calcium stores Controlled by the phosphoinositide system Hormonal stimulus splits phospholipid PIP2 into IP3 and DAG by phospholipase C BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca2+ IP3 diffuses through cytoplasm to ER. Binding of IP3 to receptor protein in ER causes Ca2+ channels to open. Ca2+ diffuses into the cytoplasm. – Ca2+ binds to calmodulin. Calmodulin activates specific protein kinase enzymes BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca2+ DAG activates protein kinase C Alters the metabolism of the cell, producing the hormone’s effects The conversion of inositol phosphate to inositol is inhibited by lithium ion treatment of manicmanic-deppressive BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca2+ BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems Second messenger systems a specific protein kinase enzyme The generation of second messengers and activation of specific protein kinase results in changes in the activity of the target cell which characterizes the response that the hormone evokes Certain receptors have intrinsic kinase activity These include receptors for growth factors, insulin, IGF,EGF, etc PROTEIN TYROSINE KINASE RECEPTORS BIOCHEMISTRY MEDICAL FACULTY USU Action of Insulin BIOCHEMISTRY MEDICAL FACULTY USU EICOSANOIDS HORMONE Roles in inflammation, fever, regulation of blood pressure, blood clotting, control of reproductive processes & tissue growth, sleep/wake cycle regulation Most affect other cells by interacting with plasma membrane GG-protein coupled receptors. BIOCHEMISTRY MEDICAL FACULTY USU Prostaglandins Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP (PGE2 and PGI2) by stimulate or inhibit adenylate cyclase PGF PGF 2 can be activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release BIOCHEMISTRY MEDICAL FACULTY USU Prostaglandins Different prostaglandins may exert antagonistic effects in some tissues. – Immune system: Promote inflammatory process. – Reproductive system: Play role in ovulation. – Digestive system: Inhibit gastric secretion – Respiratory system: May bronchoconstrict or bronchodilate. – Circulatory system: Vasoconstrictors or vasodilators. – Urinary system: BIOCHEMISTRY Vasodilation MEDICAL FACULTY USU REFERENCES Devlin T M, PhD. Text Book of Biochemistry with Clinical Correlations 5thed. WileyWiley-Liss, New York. 2002 : 906906-952, 982982-983 McKee Trudy, McKee James R. The molecular basis of Life. 3rded. McGrawMcGraw-Hill. Americas, New York. 2003 : 541541-559 Murray R K, et al. Harper’s Biochemistry 26thed. Appleton & Lange. America 2003: 434434-473 Raff A, et al. Moleculer Biology of The Cell. 4thed. Garland Science. New York. 2002: 832832-892 Stryer L. Biokimia. Edisi 4. EGC, Jakarta. 2000.: 340--358 340 BIOCHEMISTRY MEDICAL FACULTY USU