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Membrane Function Signal Transduction I. Introduction to Receptors & Signal Transduction The Players l l l l l Signaling molecules Receptors G-proteins Second messenger systems Effector proteins Signaling Molecules l l l l l Neurotransmitters Hormones Growth factors Drugs Other nomenclature Ligand Agonist / Antagonist Receptors l l l Receptors are proteins associated with cell membranes Receptors “recognize” signaling molecules by binding to them. Binding of receptors by signaling molecules ---> Cell behavior change Figure 1: Overview of Signaling Transmitters Hormones Growth Factors Hormones: Steroids Thyroid Transmitters Second Tyrosine Messangers Kinase Protein Kinases Ion Channels mRNA Synthesis Protein Synthesis Neurotansmitters: Biogenic Amines. l Catecholamines Epinephrine Norepinephrine Dopamine l l Esters: Acetylcholine Indolamines Histamine 5-HT Neurotransmitters: Peptides l l l l l Substance P Neuropeptide Y (NPY) Enkephalins Somatostatin VIP Neurotransmitters: Amino Acids l Excitatory Glutamate Aspartate l Inhibitory -aminobutyric acid (GABA) Glycine Neurotranmitters: Other l l l l l Nitric Oxide Arachadonic acid Carbon Monoxide PAF Zinc The G-Proteins l l l Involved in most signaling processes Link receptor proteins to effector proteins. Trimeric proteins composed of , , and -subunits. Figure 2: G-Protein Cycling A R A GDP A R R GTP (GTPase) -Pi A GTP R GTP Adenylate Cyclase Phospholipase C Ion Channels Phospholipase A2 Phosphodiesterase GDP Functional G-Protein Units l GTP-activated -subunit produce second messenger and/or opens ion channels. l -complexes Initially thought to be inert. Probably not inert Exact role currently ill-defined. Second messengers produced by G-protein activation. l Adenylate Cyclase cAMP l Phospholipase C (PLC) Inositol triphosphate (IP3) Diacylglycerol (DAG) l Ion Channel Activity Families of G-proteins l l l Unique structure of their -subunits. subunits appear to be similar across families. Main families: Gs Gi Gq II. cAMP Second Messenger System Figure 3: Adenylate Cyclase Ai As Adenylate Cyclase R1 R2 Gs Gi GTP GTP GDP AMP ATP-Mg++ PDE GDP cAMP C C Protein Reg Reg C C Protein Kinase A (PKA) PKA Protein-P Summary of Adenylate Cyclase Activation l Receptors which associate with Gs -type G-protein Stimulates adenylate cyclase. Increases cAMP l Receptors which associate with Gi -type G-protein Inhibit adenylate cyclase. Decreases cAMP Summary of cAMP action l l cAMP exerts its effect by activating protein kinase A (PKA) PKA phosphorylates proteins Enzymes, pumps, and channels Phosphorylation can either increase or decrease activity depending on the protein. Adenylate Cyclase l l Family of membrane spanning enzymes. Types I through IV have been well characterized. Additional types probably exist. l Types differ with respect to activity modulation by other second messenger systems Adenylate Cyclase Activity and Other Messenger Systems l l Kinases (PKA, PKC, other) can phosphorylate adenylate cyclase in some cells. Binding of adenylate cyclase by: -subunits of other G-proteins Ca++/calmodulin complexes l Allows other second messenger systems to interact with cAMP system III. The Phospholipase C Second Messenger System: IP3 and DAG Figure 4: Phospholipase C System Ca++ A PLC R Gq DAG PKC PIP2 Protein IP3 Protein-P Endoplasmic Reticulum Ca++ Summary of the Phospholipase C Messengers l l l l Agonist binds receptor Occupied Receptor ---> activation of PLC (Gq -mediated) PLC Produces second messengers: IP3 and DAG PLC activation associated with Ca++-channel activation Action of IP3 l l IP3 binds to IP3-receptors on the endoplasmic reticulum Releases intracellular Ca++ stores. Action of DAG l l l Remains membrane associated. Activates Protein kinase C (PKC) which translocates from the cytosol to the membrane Activated PKC phosphorylates other proteins and alters their function state. PLC System and Calcium l l l l PLC causes the IP3-mediated Calcium PLC also causes the influx of Ca++. Ca++ binds one of a family of Ca++ binding proteins (calmodulin). Ca++/calmodulin complex binds to yet other proteins and changes their functional activity. IV. Guanylate Cyclase: cGMP and Nitric Oxide As Second Messengers Figure 5: Nitric Oxide and cGMP Intracellular Ca++ Stores NO Synthetase Ca++ Ca++ Membrane Bound Guanylate Cyclase C.M. Ca++ NO GTP Soluble Guanylate Cyclase NO + Citrulline GTP cGMP PDE Arginine Ion Channels cGMP-Dependent PK PDEase Activity GMP NO is Membrane Soluble. l l l Diffusion to nearby cells Increase cGMP levels in nearby cells Vascular endothelial cells and nearby smooth muscle cells. V. SIGNALING BY ACETYLCHOLINE Acetylcholine As a Neurotransmitter l l Both the central and peripheral nervous systems. Binds two broad classes of receptors: Nicotinic receptors Muscarinic receptors. Nicotinic Receptor Features l Composed of 5 subunits: 2 , , and d. l l l Subunits are arranged to form a central cavity that extends across the membrane. Nicotinic receptors are also channels ACh-binding opens gates and allows ion fluxes across the channel Figure 6: Nicotinic Receptor Channel Agonist Binding Site Gate Subclasses of Nicotinic Receptors l Skeletal muscle (N1 or Nm) Unique and subunits l l Autonomic ganglia (N2 or Ng). Both N1 and N2 are gene-product families not single receptor types. Other Ligand-Gated Channels l l Structural and sequence similarity to nicotinic receptors. Example agonists for these channels include: Serotonin (5-HT) Glutamate GABA Glycine Muscarinic receptors l l l Muscarinic receptors are not channels. Operate through G-proteins to alter second messenger systems. 5 muscarinic subtypes have been cloned and sequenced (M1, M2, M3, M4, M5). Grouping Muscarinic Receptors l M1, M3, and M5 receptors: Activate Phospholipase C through Gq. PLC activation ---> increased IP3 --> increased intracellular Ca++ Increased intracellular Ca++ ---> Activation of Ca++-sensitive K+ & Clchannels. Grouping Muscarinic Receptors l M2 and M4 receptors Gi -coupled inhibition of adenylate cyclase Go or Gi -coupled regulation of certain Ca++ & K+ channels. VI. Signaling by Epinephrine and Norepinephrine and Coupling Through Adrenergic Receptors Three Families of Adrenergic Receptors: l l l -receptors: Three subtypes 1, 2, and 3. 1 -receptors: Three subtypes 1A , 1B , and 1C 2 -receptors: Three subtypes 2A , 2B , and 2C . All adrenergic receptors appear to be coupled to cellular processes through G-proteins Occupation of - Adrenergic Receptors l l l Gs-mediated stimulation of adenylate cyclase Increased cAMP Increased PKA activity. Occupation of 1 -Adrenergic Receptors l l Mechanistic details sketchy Possibly Gq-mediated PLC activation Increases IP3 and DAG for some subtypes (1B)? Activates Ca++-channels for other subtypes (1A)? Occupation of 2 -Adrenergic Receptors l l l Gi -mediated inhibition of adenylate cyclase. Decreased cAMP Decreased PKA activity.