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 Signal Chemicals Made in endocrine cells Transported via blood Receptors on target cells Long Distance Communication: Hormones Long distance cell-to-cell communication

BIOCHEMISTRY MEDICAL FACULTY USU Paracrines and Autocrines Local communication Signal chemicals diffuse to target Example: Cytokines –Autocrine–receptor on same cell –Paracrine– neighboring cells Direct and local cell-to-cell communication

BIOCHEMISTRY MEDICAL FACULTY USU Signal Pathways Signal molecule (ligand) Receptor Intracellular signal Target protein Response Signal pathways

BIOCHEMISTRY MEDICAL FACULTY USU 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: – ,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-regulation) Respond to prolonged exposure to high hormone concentrations by reducing the number of receptors (down- 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

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

BIOCHEMISTRY MEDICAL FACULTY USU 1.Cyclic AMP (cAMP) Polypeptide or glycoprotein hormones bind to receptor protein Polypeptide or glycoprotein hormones bind to receptor protein  dissociation of a subunit of G-protein The G-protein is trimer ( ,  and  subunit) The  subunit: - bound to GDP in the native G protein Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU 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 Second Messenger Systems

Activation of adenylate cyclase by binding of a hormone to its receptor

BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems - The generation of cAMP usually activates protein kinase A (PKA) - This results in activation of cAMP- dependent protein kinase (PKA) with consequent phosphorylation of target proteins 1.Cyclic AMP (cAMP) Activation of PKA

BIOCHEMISTRY MEDICAL FACULTY USU 1.Cyclic AMP (cAMP) - cAMP hydrolyzed by cAMP phosphodiesterase to 5-AMP - phosphodiesterase inhibited by methylxanthine derivatives

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 1.Cyclic AMP (cAMP) Second Messenger Systems

Action of Vasopressin/VP in Distal Kidney Tubules

BIOCHEMISTRY MEDICAL FACULTY USU 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 Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU 2. Cyclic GMP (CGMP) Atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP)  activate guanylate cyclase 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 Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU 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 light- chain kinase and renders it inactive  used to treat patients with angina Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU 3. Calcium Many cells respond to extracellular stimuli by altering their intracellular calcium concentration  interaction with calmodulin Many cells respond to extracellular stimuli by altering their intracellular calcium concentration  interaction with calmodulin Calcium levels controlled by phosphoinositide system Calcium levels controlled by phosphoinositide system Calcium ion may be more of a third messenger Calcium ion may be more of a third messenger Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU 4. Phosphoinositide/Diacylglycerol (DAG) Cytosolic calcium ion levels increased by release from intracellular calcium stores Cytosolic calcium ion levels increased by release from intracellular calcium stores Controlled by the phosphoinositide system Controlled by the phosphoinositide system Hormonal stimulus  splits phospholipid PIP 2 into IP 3 and DAG by phospholipase C Hormonal stimulus  splits phospholipid PIP 2 into IP 3 and DAG by phospholipase C Second Messenger Systems

BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca 2+ IP3 diffuses through cytoplasm to ER. Binding of IP3 to receptor protein in ER causes Ca2+ channels to open. Ca 2+ diffuses into the cytoplasm. –Ca 2+ binds to calmodulin. Calmodulin activates specific protein kinase enzymes

BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca 2+ 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 manic-deppressive

BIOCHEMISTRY MEDICAL FACULTY USU Phosphoinositide system - Ca2+

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 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

BIOCHEMISTRY MEDICAL FACULTY USU 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 G-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  2 can be activate a phosphatidylinositol signal pathway leading to intracellular Ca ++ release

BIOCHEMISTRY MEDICAL FACULTY USUProstaglandins 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: Vasodilation

BIOCHEMISTRY MEDICAL FACULTY USUREFERENCES Devlin T M, PhD. Text Book of Biochemistry with Clinical Correlations 5thed. Wiley-Liss, New York : , McKee Trudy, McKee James R. The molecular basis of Life. 3rded. McGraw-Hill. Americas, New York : Murray R K, et al. Harper’s Biochemistry 26thed. Appleton & Lange. America 2003: Raff A, et al. Moleculer Biology of The Cell. 4thed. Garland Science. New York. 2002: Stryer L. Biokimia. Edisi 4. EGC, Jakarta :