1 / 45

Membrane Function

Membrane Function. Signal Transduction. I. Introduction to Receptors & Signal Transduction. The Players. Signaling molecules Receptors G-proteins Second messenger systems Effector proteins. Signaling Molecules. Neurotransmitters Hormones Growth factors Drugs Other nomenclature

keiki
Download Presentation

Membrane Function

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Membrane Function Signal Transduction

  2. I. Introduction to Receptors & Signal Transduction

  3. The Players • Signaling molecules • Receptors • G-proteins • Second messenger systems • Effector proteins

  4. Signaling Molecules • Neurotransmitters • Hormones • Growth factors • Drugs • Other nomenclature • Ligand • Agonist / Antagonist

  5. Receptors • Receptors are proteins associated with cell membranes • Receptors “recognize” signaling molecules by binding to them. • Binding of receptors by signaling molecules ---> Cell behavior change

  6. Transmitters Hormones Transmitters Second Messangers Ion Channels Growth Factors Tyrosine Kinase Protein Kinases Hormones: Steroids Thyroid mRNA Synthesis Protein Synthesis Figure 1: Overview of Signaling

  7. Neurotansmitters: Biogenic Amines. • Catecholamines • Epinephrine • Norepinephrine • Dopamine • Esters: Acetylcholine • Indolamines • Histamine • 5-HT

  8. Neurotransmitters: Peptides • Substance P • Neuropeptide Y (NPY) • Enkephalins • Somatostatin • VIP

  9. Neurotransmitters: Amino Acids • Excitatory • Glutamate • Aspartate • Inhibitory • g-aminobutyric acid (GABA) • Glycine

  10. Neurotranmitters: Other • Nitric Oxide • Arachadonic acid • Carbon Monoxide • PAF • Zinc

  11. The G-Proteins • Involved in most signaling processes • Link receptor proteins to effector proteins. • Trimeric proteins composed of a, b, and g-subunits.

  12. A R b a g A GDP A R R b b a a g g GTP A GTP (GTPase) GDP -Pi R b a g GTP Adenylate Cyclase Phospholipase C Ion Channels Phospholipase A2 Phosphodiesterase Figure 2: G-Protein Cycling

  13. Functional G-Protein Units • GTP-activated a-subunit • produce second messenger • and/or opens ion channels. • bg-complexes • Initially thought to be inert. • Probably not inert • Exact role currently ill-defined.

  14. Second messengers produced by G-protein activation. • Adenylate Cyclase • cAMP • Phospholipase C (PLC) • Inositol triphosphate (IP3) • Diacylglycerol (DAG) • Ion Channel Activity

  15. Families of G-proteins • Unique structure of their a-subunits. • bg subunits appear to be similar across families. • Main families: • Gas • Gai • Gaq

  16. II. cAMP Second Messenger System

  17. Ai As Adenylate Cyclase R2 R1 Gs Gi GTP GTP GDP GDP ATP-Mg++ cAMP AMP PDE Protein C C Reg Reg C C Protein Kinase A (PKA) PKA Protein-P Figure 3: Adenylate Cyclase

  18. Summary of Adenylate Cyclase Activation • Receptors which associate with Gs -type G-protein • Stimulates adenylate cyclase. • Increases cAMP • Receptors which associate with Gi -type G-protein • Inhibit adenylate cyclase. • Decreases cAMP

  19. Summary of cAMP action • 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.

  20. Adenylate Cyclase • Family of membrane spanning enzymes. • Types I through IV have been well characterized. • Additional types probably exist. • Types differ with respect to activity modulation by other second messenger systems

  21. Adenylate Cyclase Activity and Other Messenger Systems • Kinases (PKA, PKC, other) can phosphorylate adenylate cyclase in some cells. • Binding of adenylate cyclase by: • bg-subunits of other G-proteins • Ca++/calmodulin complexes • Allows other second messenger systems to interact with cAMP system

  22. III. The Phospholipase C Second Messenger System: IP3 and DAG

  23. Ca++ A R PLC Gq DAG PKC PIP2 Protein Protein-P IP3 Endoplasmic Reticulum Ca++ Figure 4: Phospholipase C System

  24. Summary of the Phospholipase C Messengers • Agonist binds receptor • Occupied Receptor ---> activation of PLC (Gq -mediated) • PLC Produces second messengers: IP3 and DAG • PLC activation associated with Ca++-channel activation

  25. Action of IP3 • IP3 binds to IP3-receptors on the endoplasmic reticulum • Releases intracellular Ca++ stores.

  26. Action of DAG • 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.

  27. PLC System and Calcium • 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.

  28. IV. Guanylate Cyclase: cGMP and Nitric Oxide As Second Messengers

  29. Intracellular Ca++ Stores Ca++ Membrane Bound Guanylate Cyclase C.M. Ca++ NO GTP Ca++ Soluble Guanylate Cyclase NO NO Synthetase + Citrulline GTP PDE GMP cGMP Arginine Ion Channels cGMP-Dependent PK PDEase Activity Figure 5: Nitric Oxide and cGMP

  30. NO is Membrane Soluble. • Diffusion to nearby cells • Increase cGMP levels in nearby cells • Vascular endothelial cells and nearby smooth muscle cells.

  31. V. SIGNALING BY ACETYLCHOLINE

  32. Acetylcholine As a Neurotransmitter • Both the central and peripheral nervous systems. • Binds two broad classes of receptors: • Nicotinic receptors • Muscarinic receptors.

  33. Nicotinic Receptor Features • Composed of 5 subunits: • 2 a, b, g and d. • 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

  34. Channel Agonist Binding Site Gate Figure 6: Nicotinic Receptor

  35. Subclasses of Nicotinic Receptors • Skeletal muscle (N1 or Nm) • Unique a and b subunits • Autonomic ganglia (N2 or Ng). • Both N1 and N2 are gene-product families not single receptor types.

  36. Other Ligand-Gated Channels • Structural and sequence similarity to nicotinic receptors. • Example agonists for these channels include: • Serotonin (5-HT) • Glutamate • GABA • Glycine

  37. Muscarinic receptors • 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).

  38. Grouping Muscarinic Receptors • 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+ & Cl- channels.

  39. Grouping Muscarinic Receptors • M2 and M4 receptors • Gi -coupled inhibition of adenylate cyclase • Go or Gi -coupled regulation of certain Ca++ & K+ channels.

  40. VI. Signaling by Epinephrine and Norepinephrine and Coupling Through Adrenergic Receptors

  41. Three Families of Adrenergic Receptors: • b -receptors: Three subtypes b1, b2, and b3. • a1 -receptors: Three subtypes a1A, a1B , and a1C • a2 -receptors: Three subtypes a2A ,a2B ,and a2C

  42. . All adrenergic receptors appear to be coupled to cellular processes through G-proteins

  43. Occupation of b - Adrenergic Receptors • Gs-mediated stimulation of adenylate cyclase • Increased cAMP • Increased PKA activity.

  44. Occupation of a1 -Adrenergic Receptors • Mechanistic details sketchy • Possibly Gq-mediated PLC activation • Increases IP3 and DAG for some subtypes (1B)? • Activates Ca++-channels for other subtypes (1A)?

  45. Occupation of a2 -Adrenergic Receptors • Gi -mediated inhibition of adenylate cyclase. • Decreased cAMP • Decreased PKA activity.

More Related