GTPases in Biology

Section IV: Signal Transduction by Trimeric G Proteins.- A. Cellular Architecture and its Role in Signal Transduction.- 44 G-Proteins Have Properties of Multimeric Proteins: An Explanation for the Role of GTPases in their Dynamic Behavior.- A. Introduction.- B. Theories.- I. Shuttle Theory.- II. Collision-coupling Theory.- III. Disaggregation Theory.- C. Evidence for Multimeric Structures of G-Proteins.- I. Properties in Detergents.- II. Cross-Linking of G-Proteins in Membranes.- III. Glucagon Activation of Multimeric Gs in Hepatic Membranes.- D. Coupling of Receptors to Multimeric G-Proteins.- E. Hydrolysis of GTP Is Fundamental to Signal Transduction Dynamics.- F. Conclusions.- References.- B. G-Protein Coupled Receptors.- 45 The Superfamily: Molecular Modelling.- A. Introduction.- B. General Principles - Modelling Integral Membrane Domains.- I. Summary of Information Available for G-Protein-Coupled Receptor Modelling Studies.- C. Modelling G-Protein-Coupled Receptors from Sequence Alignments.- I. Sequence Comparisons.- II. Fourier Transform Analysis of G-Protein-Coupled Receptor Sequence Alignments.- 1. Prediction of Structural Environments from Sequence Alignments.- 2. Detection of Periodicity and the Discrimination of the Different Sides of the Helix.- 3. Detection of the Ends of the Transmembrane Regions of the Helices.- 4. Summary of Methodology.- 5. Application to G-Protein-Coupled Receptors.- D. Three-Dimensional Models of G-Protein-Coupled Receptors.- I. Construction of G-Protein-Coupled Receptor Models Based on the Fourier Transform Predictions.- II. Analysis of the Models.- References.- 46 The Role of Receptor Kinases and Arrestin-Like Proteins in G-Protein-Linked Receptor Desensitization.- References.- C. Trimeric G-Proteins.- 47 Qualitative and Quantitative Characterization of the Distribution of G-Protein ? Subunits in Mammals.- A. Introduction.- B. Identification of G-Protein ? Subunits.- I. [32P]ADP Ribosylation.- II. Immunological Determination of G-Protein Distribution.- C. Immunological Determination of G-Protein ? Subunit Levels.- I. Quantitative and Relative Intensity Immunoblotting.- II. ELISA.- III. Other Approaches.- D. Asymmetric Distribution of G-Proteins in the Plasma Membrane.- E. Conclusions.- References.- 48 Subunit Interactions of Heterotrimeric G-Proteins.- A. Signalling by ? and ?? Subunits.- I. Effect of Subunit Association on the Guanine Nucleotide Binding and GTPase Activity.- II. Physical Properties of Associated and Dissociated G-Protein Subunits.- III. The ? and ?? Interface.- 1. Analysis by Site-Directed Mutagenesis of Requirments for ? and ?? Interactions.- 2. Analysis of ?? Contact Regions by Cross-Linking.- 3. Probing the ? and ?? Interface with Antibodies.- IV. Does Dissociation of ? and ?? Occur in the Plasma Membrane?.- B. Interaction of ? and ? Subunits.- I. Site of Interaction of ?1 with ?1 and ?2.- C. Specificity of Interaction Between Particular ? and ?? Combinations.- References.- 49 G-Protein ? Subunit Chimeras Reveal Specific Regulatory Domains Encoded in the Primary Sequence.- A. Background.- B. Mutational Analysis of the GDP/GTP Binding Domain.- C. Competitive Inhibitory Mutations.- D. Regulatory Properties of the ?s N Terminus.- E. ?i2/?s Chimeras Reveal the Regulatory Function of the ? Subunit N Terminus.- F. Mutations that Influence GDP Dissociation and GTPase Activity Create Strong Constitutively Active ?s Polypeptides.- G. Sites of ?? Subunit Interactions.- H. Mapping of the ?s Adenylyl Cyclase Activation Domain.- I. Conclusions.- References.- 50 The GTPase Cycle: Transducin.- A. The Retinal cGMP Cascade and Visual Excitation.- B. The Coupling Cycle of Transducin.- C. The Reaction Dynamics of the Transducin Cycle.- I. Transducin Subunit Interaction.- II. Pre-Steady-State Kinetic Analysis of the GTP Hydrolysis Reaction.- III. Quantitative Analysis of the Pre-Steady-State Kinetics.- D. Relationship of GTP Hydrolysis and PDE Deactivation.- E. Regulation of the Transducin Coupling Cycle by Phosducin.- F. Concluding Remarks.- References.- 51 Transcriptional, Posttranscriptional, and Posttranslational Regulation of G-Proteins and Adrenergic Receptors.- A. Introduction.- B. Agonist-Induced Regulation of Transmembrane Signaling.- I. Transcriptional and Posttranscriptional Regulation.- II. Posttranslational Regulation.- C. Cross-Regulation in Transmembrane Signaling.- I. Stimulatory to Inhibitory Adenylyl Cyclase.- II. Inhibitory to Stimulatory Adenylyl Cyclase.- III. Stimulatory Adenylyl Cyclase to Phospholipase C.- IV. Tyrosine Kinase to Stimulatory Adenylyl Cyclase.- D. Permissive Hormone Regulation of Transmembrane Signaling.- E. Perspectives.- References.- 52 G-Protein Subunit Lipidation in Membrane Association and Signaling.- A. Introduction.- B. Myristoylation and Membrane Association of G-Protein ? Subunits.- I. Cotranslational Processing of G-Protein ? Subunits.- II. The Role of Myristoylation in ? Subunit-Membrane Association.- C. Prenylation and Membrane Association of G-Protein ? Subunits.- I. Posttranslational Processing of G-Protein ? Subunits.- II. The Role of Prenylation in ? Subunit-Membrane Association.- 1. Geranylgeranyl-Modified ? Subunits.- 2. Farnesyl-Modified ? Subunits.- D. Future Directions.- References.- 53 Phosphorylation of Heterotrimeric G-Protein.- A. Introduction.- I. Nature of G-Proteins.- II. Modulation of G-Protein Action.- 1. Phosphorylation.- B. Phosphorylation of Heterotrimeric G-proteins in Intact Cells.- I. Hepatocytes.- II. Promonocytic Cell Line U937.- III. Platelets.- 1. Gi-2.- 2. Gz.- IV. Yeast.- V. Dictyostelium.- C. In Vitro Phosphorylation of Isolated Heterotrimeric G-Proteins.- I. Transducin.- II. Gi and Go.- III. Gs.- IV. Unidentified "G-Proteins".- D. Conclusion.- References.- 54 Receptor to Effector Signaling Through G-Proteins: ?? Dimers Join ? Subunits in the World of Higher Eukaryotes.- A. Introduction.- B. ?? Dimers and Adenylyl Cyclase.- I. Hormonal Inhibition of Adenylyl Cyclase and Stimulation of K+ Channels: Controversies that Settled Mostly in Favor of ? Subunits.- II. Conditional and Subtype-Specific Regulation of Adenylyl Cyclase Activity by ?? Dimers.- C. ?? Dimers and Phospholipase C: Subtype-Specific Stimulation of Type ? Phospholipase C by ?? Dimers.- D. ?? Dimers and Receptors: Exquisite Specificity of Receptors for ?? Subtypes.- E. Dual Signaling of Single Receptors: Mediation by One or by Two G-Proteins?.- I. Inhibition of Adenylyl Cyclase and Stimulation of Phospholipase C.- II. Signaling Quality Through Receptor Quantity?.- III. Dual Stimulation of Adenylyl Cyclase and Phospholipase C.- IV. Evidence for Physical Interaction of a Single Receptor with Two Distinct Types of G-Proteins.- F. The Puzzle of the Up-Shifted Dose-Response Curves for Phospholipase C Elicited by Adenylyl Cyclase Stimulating Agonists.- G. Concluding Remarks.- References.- D. Effectors of G-Proteins.- 55 Molecular Diversity of Mammalian Adenylyl Cyclases: Functional Consequences.- A. Introduction.- B. Stimulation and Inhibition of Adenylyl Cyclases.- C. Molecular Diversity of Adenylyl Cyclases.- I. Multiple Families of Adenylyl Cyclases.- II. Secondary Structure and Topography.- III. Putative Catalytic Sites.- IV. Tissue Distribution of the Various Forms.- D. G-Protein Regulation of Adenylyl Cyclases.- I. Gs-? Regulation.- II. Gi-? Regulation.- III. ?? Regulation.- E. Type-Specific Regulation by Intracellular Ligands.- I. Ca2+/CaM Regulation.- II. Inhibition by Low Concentrations of Ca2+.- III. P-Site Inhibition.- F. Regulation by Protein Phosphorylation.- I. Regulation by Protein Kinase C.- II. Protein Kinase A Regulation: A Component of Heterologous Desensitization.- G. Functional Consequences of Multiple Adenylyl Cyclases.- I. Integration of Multiple Signals.- II. Modulation of Signal Transmission.- References.- 56 The Light-Regulated cGMP Phosphodiesterase of Vertebrate Photoreceptors: Structure and Mechanism of Activation by Gt?.- A. Physiological Role of cGMP Phosphodiesterase in Visual Signaling.- B. Structure.- I. Subunit Composition.- II. Size and Hydrodynamic Properties.- III. Primary Structure.- IV. Posttranslational Modifications.- V. Domain Structures of Subunits.- 1. Catalytic Subunits.- 2. Inhibitory Subunit.- C. Functional Properties.- I. Solubility.- II. Kinetic Properties.- III. Noncatalytic cGMP Binding Sites.- D. Regulation of Catalytic Activity.- I. Inhibition by PDE?.- II. Activation by G-Protein.- 1. Role of Gt?.- 2. Role of Membranes in PDE Activation by Gt?.- 3. Role of PDE? in Activation by Transducin.- 4. Is There Cooperativity in the Action of Gt?-GTP?.- 5. A Role for Noncatalytic cGMP Binding Sites?.- References.- 57 High-Voltage Activated Ca2+ Channel.- A. Introduction.- B. Identified cDNAs of High-Voltage Activated Calcium Channels.- I. The ?1 Subunit.- II. The ?2/? Subunit.- III. The ? Subunit.- IV. The ? Subunit.- C. Structure-Function of the Cloned Calcium Channel Proteins.- I. Expression and Function of the Channel Subunits.- II. The Binding Sites for Calcium Channel Blockers.- III. Phosphorylation of the Channel Proteins.- D. Conclusion.- References.- 58 Phospholipase C-? Isozymes Activated by G?q Members.- References.- 59 Stimulation of Phospholipase C by G-Protein ?? Subunits.- A. Introduction.- B. Stimulation of Soluble Phospholipase C of HL-60 Granulocytes by G-Protein ?? Subunits.- C. Identification of the ??-Sensitive Phospholipase C of HL-60 Granulocytes as PLC?2.- D. Stimulation of PLC?2 by G-Protein ?? Subunits in Intact Cells.- E. Role of ?? Subunits in Mediating Receptor Stimulation of Phospholipase C.- F. Perspectives.- References.- E. Specialized Systems.- 60 Rhodopsin/G-Protein Interaction.- A. Introduction.- B. Interactions of Rhodopsin in the Visual Cascade.- C. Biophysical Monitors of G-Protein Activation.- I. Description of the Monitors.- II. Instrumentation.- III. Application to the Analysis of R*-Gt Interaction.- IV. Preparations.- D. Interactive States of Rhodopsin.- I. Molecular Nature of Metarhodopsin II.- II. Active Forms of Rhodopsin from Alternative Light-Induced Pathways.- III. Activation of Rhodopsin in the Dark.- E. Interactive States of Transducin.- I. Dark Binding.- II. Stable Light Binding with Empty Nucleotide Site.- III. Rhodopsin/G-Protein Interaction with Bound Nucleotides.- F. Mechanism of Transducin Activation.- I. Role of Rhodopsin's Cytoplasmic Loops.- 1. Three Loops Contribute to MII-Gt Interaction.- 2. Loop Mutants: Binding and Activation in MII-Gt Interaction.- II. Dissection of Reaction Steps.- 1. The GDP/MII Switch.- 2. The MII/GTP Switch.- III. Regulation of the Activation Pathway.- G. Conclusion.- References.- 61 Fast Kinetics of G-Protein Function In Vivo.- A. Introduction.- B. Kinetics of Muscarinic K+ Channel Activation.- C. Rapid Desensitization.- D. Kinetics of IK(ACh) Deactivation.- E. Basic Kinetic Model for Membrane-Delimited Effector Activation by a G-Protein.- F. Conclusions.- References.- 62 The Yeast Pheromone Response G-Protein.- A. Introduction.- B. Overview.- C. Gpal, the G? Subunit.- I. Random Mutagenesis.- II. Site-Directed Mutagenesis.- D. Ste4, the G? Subunit.- I. Random Mutagenesis.- II. Site-Directed Mutagenesis.- E. Ste18, the G? Subunit.- I. Random Mutagenesis.- II. Site-Directed Mutagenesis.- F. Conclusions.- References.- 63 Ga Proteins in Drosophila: Structure and Developmental Expression.- A. Introduction.- I. G-Protein-Coupled Signaling in Development.- II. The Drosophila System.- B. G?-Proteins in Drosophila.- I. DGs?.- 1. Gene Structure.- 2. Adult and Embryonic Expression.- 3. Stimulation of Mammalian Adenylyl Cyclase Through DGs?.- II. DGo?.- 1. Gene Structure.- 2. Adult and Embryonic Expression.- III. DGi?.- 1. Gene Structure.- 2. Adult and Embryonic Expression.- IV. DGq?.- 1. Gene Structure.- 2. Adult Expression.- 3. Role in Phototransduction.- V. concertina.- 1. Mutant Phenotype.- 2. Cloning and Gene Structure.- 3. Expression of cta.- C. Summary.- References.- 64 Signal Transduction by G-Proteins in Dictyostelium discoideum.- A. Introduction.- B. Signal Transduction in Dictyostelium.- C. Diversity of G-Proteins in Dictyostelium.- D. Roles of G-Proteins in Signal Transduction Processes.- E. Roles of G-Proteins in Morphogenesis and Differentiation.- F. Conclusions and Perspectives.- References.- 65 Functional Expression of Mammalian Receptors and G-Proteins in Yeast.- A. Introduction.- B. Expression of Mammalian G-Protein-Coupled Receptors.- C. Expression of Mammalian G-Protein Subunits.- I. Physiological Roles of Yeast G-Protein Subunits.- II. Mammalian G? Subunits.- 1. Intact G? Subunits.- 2. Chimeric Yeast/Mammalian G? Subunits.- III. Mammalian G? and G? Subunits.- D. Signaling Between Mammalian Receptors and G-Proteins.- E. Perspectives.- References.- 66 G-Proteins in the Signal Transduction of the Neutrophil.- A. Introduction.- B. Receptor-Mediated PMN Functions.- I. Adherence.- II. Chemotaxis.- III. Phagocytosis and Bactericidal Activity.- IV. Regulatory Receptors.- C. G-Protein-Coupled Receptors.- I. Chemoattractant Receptors.- II. Purinergic Receptors.- III. Other PMN Receptors.- D. Regulation of Neutrophil Responses.- I. Priming.- II. Desensitization.- References.- 67 Hormonal Regulation of Phospholipid Metabolism via G-Proteins: Phosphoinositide Phospholipase C and Phosphatidylcholine Phospholipase D.- A. Introduction.- B. Identification of the G-Proteins Regulating PtdInsP2 Phospholipase C.- C. Coupling of G-Proteins to Ca2+-Mobilizing Receptors.- D. Specificity of Phosphoinositide Phospholipase C Linked to Gq and G11.- E. Mechanisms of Agonist-Stimulated Phosphatidylcholine Breakdown.- F. Summary.- References.- 68 Hormonal Regulation of Phospholipid Metabolism via G-proteins II: PLA2 and Inhibitory Regulation of PLC.- A. Introduction.- B. Modulation of PLA2.- I. Molecular Forms of PLA2.- II. G-Protein-Mediated Activation of PLA2.- III. Molecular Aspects.- IV. Inhibitory Regulation of PLA2.- C. Activity of PLA2 in ras-Transformed Cells.- D. Inhibitory Regulation of PLC.- I. Molecular Aspects.- E. Conclusion.- References.- 69 G-Protein Regulation of Phospholipase C in the Turkey Erythrocyte.- A. Introduction.- B. Properties of P2Y Purinergic Receptor and G-Protein-Regulated PLC in Turkey Erythrocytes.- I. Initial Observations.- II. Kinetics of Activation of PLC by P2Y Purinergic Receptor Agonists and Guanine Nucleotides.- C. Identification, Purification, and Primary Structure of the Protein Components of the Turkey Erythrocyte Inositol Lipid-Dependent Signaling System.- I. G-Protein-Regulated PLC.- 1. Purification and Properties of a G-Protein-Regulated PLC from Turkey Erythrocytes.- 2. Receptor and G-Protein Regulation of the Purified Turkey Erythrocyte PLC.- II. G-Protein Activators of PLC.- 1. Purification and Properties of the Turkey Erythrocyte PLC-Activating G-Protein.- 2. cDNA Sequence of the Turkey Erythrocyte PLC-Activating G-Protein and its Relationship to Mammalian G-Protein ? Subunits.- D. Concluding Comments.- References.- 70 Hormonal Inhibition of Adenylyl Cyclase by ?i and?? ?i or ?? ?i and/or ??.- A. Introduction.- B. Mechanism(s) Mediating Inhibition of Adenylyl Cyclase.- I. Direct Inhibition of Adenylyl Cyclase by ?i.- II. Indirect Inhibition of Adenylyl Cyclase by ?? Suppression of ?s Activation.- III. Direct Inhibition of Adenylyl Cyclase by ??.- C. Current View of Inhibition of Adenylyl Cyclase.- I. The Mechanism of Inhibition of Adenylyl Cyclase in S49 Cells.- II. Significance and Predications of Multiple Mechanism fo Inhibition.- III. Unresolved Structural and Functional Issues about G-proteins Affecting the Mechanism(s) Mediating Hormone Inhibition of Adenylyl Cyclase.- D. Conclusion.- References.- 71 Neurobiology of Go.- A. Introduction.- B. Gene Structure of Go? in Vertebrates and Invertebrates.- I. Gene Structure and Transcription in Vertebrates.- II. Gene Structure and Transcription in Invertebrates.- C. Cellular Expression of Go in Excitable Cells and Its Regulation.- I. Cellular and Subcellular Distribution.- 1. Neurons.- 2. Nonneuronal Cells.- II. Control of Go, Go1, and Go2 Expression During Neuronal Differentiation.- D. Neurotransmitter Receptors Coupled to Go and Their Inhibitory Effects on Voltage-Sensitive Ca2+ Channels.- I. Nature of Receptors.- 1. Reconstitution of Resolved Receptors and Go-Proteins.- 2. Reconstitution of Receptor Coupling to VSCC with Go-Protein in PTX-Treated Cells.- 3. Stimulation of Go Photolabeling with [?32-P]GTP Azidoanilide by Neurotransmitters.- 4. Intracellular Injections of G-protein Antibodies and of Antisense Oligonucleotides Complementary to G-Protein or DNA Sequences To Demonstrate the Specificity of the Negative Coupling Between Receptors and VSCC via Go.- 5. Immunoprecipitation of Receptor-Go Complexes with Anti-Go Antibodies and Anti-receptor Antibodies.- II. Nature of VSCC Inhibited by Go.- III. Colocalization of Go and L-Type VSCC in T-Tubule.- IV. Conclusions.- E. General Conclusion.- References.- 72 Involvement of Pertussis-Toxin-Sensitive G-Proteins in the Modulation of Ca2+ Channels by Hormones and Neurotransmitters.- A. Introduction.- B. Inhibitory Modulation of Voltage-Dependent Ca2+ Channels.- I. Occurrence; Physiological Significance.- II. Effects of Receptor Agonists, Pertussis Toxin, and Guanine Nucleotides.- III. Types of Ca2+ Channels Affected by Inhibitory Receptor Agonists.- IV. Mechanistic Aspects.- 1. Cyclic Nucleotides.- 2. Protein Kinase C and Fatty Acids.- 3. Evidence for a Membrane-Delimited Pathway.- V. Identification of the Involved G-Protein.- 1. Occurrence of Go.- 2. Reconstitution Experiments with Native and Recombinant G-Proteins; Transfected Cells.- 3. Antibodies.- 4. Go-Activating Receptors.- 5. Antisense Oligonucleotides.- C. Stimulatory Modulation of Voltage-Dependent Ca2+ Channels.- I. Occurrence; Physiological Significance.- II. Effects of Pertussis Toxin and Guanine Nucleotides.- III. Types of Ca2+ Currents Affected by Stimulatory Receptor Agonists.- IV. Mechanistic Aspects.- V. Identity of the G-Protein Involved.- D. Conclusion.- References.- 73 Regulation of Cell Growth and Proliferation by Go.- A. Introduction.- B. The Go-Protein.- C. The Go-Protein and Cell Cycle Regulation in the Xenopus Oocyte.- D. Regulation of Oocyte Maturation by Multiple Pathways.- E. Proliferation of Mammalian Cells by Activated Go.- F. Specificity of Transformation by Signaling Through G-Protein Pathways.- G. Desensitization and Growth Signaling Through G-Protein Pathways.- References.- 74 Role of Nucleoside Diphosphate Kinase in G-Protein Action.- A. Introduction.- B. General Model of Membrane Signaling Systems Involving G-Proteins.- C. Role of NDP Kinase in Membrane Signaling Systems.- I. Evaluation of the Effect of GDP in Comparison with GTP.- II. Role of mNDP Kinase in Signal Transduction.- III. Comparison Between Hormone and Cholera Toxin Actions.- IV. Interaction Between mNDP Kinase and Gs and Its Regulation.- V. Regulatory Mechanism of G-Protein by NDP Kinase.- VI. Physiological Relevance of G-Protein Regulation by mNDP Kinase.- D. Properties of NDP Kinases and Their Structure.- E. Novel Roles of NDP Kinases in Cellular Functions.- F. Concluding Remarks.- References.- 75 G-Protein Regulation of Cardiac K+ Channels.- A. Introduction.- B. Involvement of G-Protein in Muscarinic Activation of the KACh Channel.- C. Physiological Mode of G-Protein Activation of the KACh Channel.- D. Effects of G-Protein Subunits on the Cardiac KACh Channel.- I. Comparison Between the Regulation of Adenylyl Cyclase Activity and the KACh Channel Activity by Purified G-Protein Subunits.- II. Effects of G?? on the KACh Channel.- 1. Voltage-Dependent Properties of the G??-Activated KACh Channel.- 2. Concentration Dependence of G?? Activation of the KACh Channel.- 3. Specificitiy of G?? Activation of the KACh Channel.- 4. G?? Activation of the KACh Channel Is Not Mediated by Phospholipase A2.- 5. Antibody 4A Does Not Inhibit the Interaction Between GK and the KACh Channel.- III. Effects of G-Protein on the ATP-Sensitive K Channel.- E. Stimulatory Modulation of the GK-Gated Cardiac KACh Channel.- I. Arachidonic Acid and Its Metabolites.- II. Phosphorylation.- III. NDP-Kinase.- IV. Intracellular Chloride.- F. Conclusion.- References.- 76 Modulation of K+ Channels by G-Proteins.- A. Direct Regulation of Ionic Channels by G-Proteins.- I. The Inwardly Rectifying "Muscarinic" K+ Channel.- 1. Experiments Leading to the Discovery of G-Protein Gating.- 2. Direct Stimulation by hRBC Gi and Its ? Subunit.- 3. Properties of the Gi-stimulated K+ Channel.- 4. Identity of the Gk that Gates the Muscarinic-Type K+ Channels.- II. The ATP-Sensitive K+ Channel: A Second Gi-Gated K+ Channel.- 1. General Properties of the ATP-Sensitive K+ Channel/ Sulfonyliurea Receptor Complex.- 2. Identity of G-proteins that Regulate the ATP-Sensitive K+ Channel.- III. G-Protein Gating as a Tool To Discover Novel Ionic Channels: Neuronal Go-Gated K+ Channels.- B. Effect of ?? Dimers: Inhibition versus Stimulation of the Muscarinic K+ Channel - A Persisting Controversy.- C. Conclusions.- References.- 77 ATP-Sensitive K+ Channel: Properties, Occurrence, Role in Regulation of Insulin Secretion.- A. Introduction.- B. Biophysical Properties.- C. Regulation of the KATP Channel.- I. Inhibition by Intracellular Nucleotides.- II. Activation by Intracellular Nucleoside Diphosphates.- III. Activation by Intracellular MgATP.- IV. Activation by G-Proteins.- V. Inhibition by G-Proteins.- VI. Inhibition by Drugs.- VII. Activation by Drugs.- VIII. Characteristics of the Sulfonylurea Receptor.- D. Role of the KATP- Channel in Regulation of Insulin Secretion.- References.- 78 Modulation of Maxi-Calcium-Activated K Channels: Role of Ligands, Phosphorylation, and G-Proteins.- A. Introduction.- B. Mechanisms of Metabolic Regulation of Maxi-KCa Channels.- I. Ligand Modulation.- 1. Arachidonic Acid.- 2. Angiotensin II and Thromboxane A2.- 3. Guanine Nucleotides.- 4. Intracellular pH.- II. Phosphorylation/Dephosphorylation Cycles.- 1. Pituitary Maxi-KCa Channels.- 2. Brain Maxi-KCa Channels.- 3. Colonic Maxi-KCa Channels.- 4. Myometrial Maxi-KCa Channels.- III. G-Protein Gating.- 1. Muscarinic Regulation.- 2. Adrenergic Stimulation.- C. Conclusions.- References.- 79 Regulation of the Endosomal Proton Translocating ATPase (H+-ATPase) and Endosomal Acidification by G-Proteins.- A. Introduction.- B. Endocytosis.- I. General.- II. The Kidney.- C. Endosomal Acidification.- I. Potential Role for G-Proteins in Endosomal Acidification.- II. Effects of G-Proteins on Endosomal Acidification.- D. Conclusions.- References.- 80 cAMP-Independent Regulation of Adipocyte Glucose Transport Activity and Other Metabolic Processes by a Complex of Receptors and their Associated G-Proteins.- A. Introduction.- B. Lack of a Relationship Between cAMP and Glucose Transporter Activity.- C. G-Proteins in Glucose Transporter Regulation.- D. How Do G-Proteins Mediate Glucose Transporter Activity?.- E. Other RSGS- and RiGiMediated Processes in Adipocytes.- F. Conclusions and Speculations.- References.