The Many Faces of G Protein Signaling*

A large number of hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells and organisms by binding to G protein-coupled receptors. More than a thousand such receptors are known, and more are being discovered all the time. Heterotrimeric G proteins transduce ligand binding to these receptors into intracellular responses, which underlie physiological responses of tissues and organisms. G proteins play important roles in determining the specificity and temporal characteristics of the cellular responses to signals. They are made up of a, b, and g subunits, and although there are many gene products encoding each subunit (20 a, 6 b, and 12 g gene products are known), four main classes of G proteins can be distinguished: Gs, which activates adenylyl cyclase; Gi, which inhibits adenylyl cyclase; Gq, which activates phospholipase C; and G12 and G13, of unknown function. G proteins are inactive in the GDP-bound, heterotrimeric state and are activated by receptor-catalyzed guanine nucleotide exchange resulting in GTP binding to the a subunit. GTP binding leads to dissociation of GazGTP from Gbg subunits and activation of downstream effectors by both GazGTP and free Gbg subunits. G protein deactivation is rate-limiting for turnoff of the cellular response and occurs when the Ga subunit hydrolyzes GTP to GDP. The recent resolution of crystal structures of heterotrimeric G proteins in inactive and active conformations provides a structural framework for understanding their role as conformational switches in signaling pathways. As more and more novel pathways that use G proteins emerge, recognition of the diversity of regulatory mechanisms of G protein signaling is also increasing. The recent progress in the structure, mechanisms, and regulation of G protein signaling pathways is the subject of this review. Because of space considerations, I will concentrate mainly on recent studies; readers are directed to a number of excellent reviews that cover earlier studies.

[1]  M. Simon,et al.  A Novel Form of the G Protein β Subunit Gβ5 Is Specifically Expressed in the Vertebrate Retina* , 1996, The Journal of Biological Chemistry.

[2]  R. Neubig,et al.  Receptor and Membrane Interaction Sites on G , 1996, The Journal of Biological Chemistry.

[3]  J. Wess.  G‐protein‐coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G‐protein recognition , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  M. Kunkel,et al.  Identification of domains conferring G protein regulation on inward rectifier potassium channels , 1995, Cell.

[5]  W. Catterall,et al.  Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α1A subunit , 1997 .

[6]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[7]  M. Lohse,et al.  A small region in phosducin inhibits G‐protein βγ‐subunit function , 1997 .

[8]  B. Shieh,et al.  Regulation of the TRP Ca2+ Channel by INAD in Drosophila Photoreceptors , 1996, Neuron.

[9]  A. Gohla,et al.  Interaction of G protein Gβγ dimers with small GTP‐binding proteins of the Rho family , 1996 .

[10]  P. Insel,et al.  Interaction of the protein nucleobindin with Gαi2, as revealed by the yeast two‐hybrid system , 1995 .

[11]  J. Frost,et al.  The Monomeric G-Proteins Rac1 and/or Cdc42 Are Required for the Inhibition of Voltage-Dependent Calcium Current by Bradykinin , 1997, The Journal of Neuroscience.

[12]  M. Franco,et al.  The small G‐protein ARF1GDP binds to the G t βγ subunit of transducin, but not to Gt α GDP‐Gt βγ , 1995 .

[13]  H. Hamm,et al.  The 2.0 Å crystal structure of a heterotrimeric G protein , 1996, Nature.

[14]  Andrew Bohm,et al.  Crystal structure of a GA protein βγdimer at 2.1 Å resolution , 1996, Nature.

[15]  Stefan Offermanns,et al.  Vascular System Defects and Impaired Cell Chemokinesis as a Result of Gα13 Deficiency , 1997, Science.

[16]  H. Bourne,et al.  How receptors talk to trimeric G proteins. , 1997, Current opinion in cell biology.

[17]  S R Sprang,et al.  G protein mechanisms: insights from structural analysis. , 1997, Annual review of biochemistry.

[18]  H. Khorana,et al.  Structural features and light-dependent changes in the cytoplasmic interhelical E-F loop region of rhodopsin: a site-directed spin-labeling study. , 1996, Biochemistry.

[19]  Heidi E. Hamm,et al.  Structural determinants for activation of the α-subunit of a heterotrimeric G protein , 1994, Nature.

[20]  R. Jove,et al.  A Direct Interaction between G-Protein βγ Subunits and the Raf-1 Protein Kinase (*) , 1995, The Journal of Biological Chemistry.

[21]  Xin-Yun Huang,et al.  Direct stimulation of Bruton's tyrosine kinase by Gq-protein α-subunit , 1997, Nature.

[22]  M. Ermolaeva,et al.  Receptor-G protein coupling is established by a potential conformational switch in the beta gamma complex. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W. Simonds,et al.  The coiled-coil region of the G protein beta subunit. Mutational analysis of Ggamma and effector interactions. , 1997, The Journal of biological chemistry.

[24]  S. Ikeda.  Voltage-dependent modulation of N-type calcium channels by G-protein β γsubunits , 1996, Nature.

[25]  M. Lindorfer,et al.  Role of the Prenyl Group on the G Protein γ Subunit in Coupling Trimeric G Proteins to A1 Adenosine Receptors* , 1996, The Journal of Biological Chemistry.

[26]  Y. Wan,et al.  Activation of Tsk and Btk tyrosine kinases by G protein beta gamma subunits. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Tsien,et al.  Multiple Structural Elements in Voltage-Dependent Ca2+ Channels Support Their Inhibition by G Proteins , 1996, Neuron.

[28]  H. Hamm,et al.  Molecular Determinants of Selectivity in 5-Hydroxytryptamine1B Receptor-G Protein Interactions* , 1997, The Journal of Biological Chemistry.

[29]  K. Page,et al.  The Intracellular Loop between Domains I and II of the B-Type Calcium Channel Confers Aspects of G-Protein Sensitivity to the E-Type Calcium Channel , 1997, The Journal of Neuroscience.

[30]  Gebhard F. X. Schertler,et al.  Arrangement of rhodopsin transmembrane α-helices , 1997, Nature.

[31]  E. Stefani,et al.  Direct interaction of Gβγ with a C-terminal Gβγ-binding domain of the Ca2+ channel α1 subunit is responsible for channel inhibition by G protein-coupled receptors , 1997 .

[32]  R. Stoffel,et al.  A region of adenylyl cyclase 2 critical for regulation by G protein beta gamma subunits. , 1995, Science.

[33]  D. Clapham,et al.  The G-protein-gated atrial K+ channel IKAch is a heteromultimer of two inwardly rectifying K+-channel proteins , 1995, Nature.

[34]  K. Jakobs,et al.  G protein specificity in receptor-effector coupling. Analysis of the roles of G0 and Gi2 in GH4C1 pituitary cells. , 1994, The Journal of biological chemistry.

[35]  J. Hildebrandt,et al.  Role of subunit diversity in signaling by heterotrimeric G proteins. , 1997, Biochemical pharmacology.

[36]  Y. Jan,et al.  Evidence that direct binding of Gβγ to the GIRK1 G protein-gated inwardly rectifying K+ channel is important for channel activation , 1995, Neuron.

[37]  A. Barr,et al.  Reconstitution of Receptors and GTP-binding Regulatory Proteins (G Proteins) in Sf9 Cells , 1997, The Journal of Biological Chemistry.

[38]  K. Clark,et al.  Association of the yeast pheromone response G protein beta gamma subunits with the MAP kinase scaffold Ste5p. , 1995, Science.

[39]  M. Miles,et al.  Interaction of Phosducin-like Protein with G Protein βγ Subunits* , 1997, The Journal of Biological Chemistry.

[40]  R. Sunahara,et al.  Complexity and diversity of mammalian adenylyl cyclases. , 1996, Annual review of pharmacology and toxicology.

[41]  T. Gudermann,et al.  Functional and structural complexity of signal transduction via G-protein-coupled receptors. , 1997, Annual review of neuroscience.

[42]  S. Reed,et al.  Role for the Rho-family GTPase Cdc42 in yeast mating-pheromone signal pathway , 1995, Nature.

[43]  Andrew Bohm,et al.  Crystal Structure at 2.4 Å Resolution of the Complex of Transducin βγ and Its Regulator, Phosducin , 1996, Cell.

[44]  A. Gobert,et al.  The transient receptor potential protein (Trp), a putative store‐operated Ca2+ channel essential for phosphoinositide‐mediated photoreception, forms a signaling complex with NorpA, InaC and InaD. , 1996, The EMBO journal.

[45]  P. Insel,et al.  Identification and cDNA cloning of a novel human mosaic protein, LGN, based on interaction with G alpha i2. , 1996, Gene.

[46]  Denise S Walker,et al.  Direct binding of G-protein βλ complex to voltage-dependent calcium channels , 1997, Nature.

[47]  Y. Kaziro,et al.  C-terminal Mutation of G Protein β Subunit Affects Differentially Extracellular Signal-regulated Kinase and c-Jun N-terminal Kinase Pathways in Human Embryonal Kidney 293 Cells* , 1997, The Journal of Biological Chemistry.

[48]  M. Saraste,et al.  FEBS Lett , 2000 .

[49]  K. Irie,et al.  Dynamics and organization of MAP kinase signal pathways , 1995, Molecular reproduction and development.

[50]  S. Sprang,et al.  Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. , 1994, Science.

[51]  H. Hamm,et al.  Interaction of Transducin with Light-activated Rhodopsin Protects It from Proteolytic Digestion by Trypsin* , 1996, The Journal of Biological Chemistry.

[52]  J. Baldwin,et al.  An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. , 1997, Journal of molecular biology.

[53]  G. Schultz,et al.  G Protein Heterotrimer Gα13β1γ3 Couples the Angiotensin AT1A Receptor to Increases in Cytoplasmic Ca2+ in Rat Portal Vein Myocytes* , 1997, The Journal of Biological Chemistry.

[54]  A. Gilman,et al.  Mammalian RGS Proteins: Barbarians at the Gate* , 1998, The Journal of Biological Chemistry.

[55]  P. Hawkins,et al.  The Gβγ Sensitivity of a PI3K Is Dependent upon a Tightly Associated Adaptor, p101 , 1997, Cell.

[56]  H. Khorana,et al.  Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin , 1996, Science.

[57]  C. Barnes,et al.  Homer: a protein that selectively binds metabotropic glutamate receptors , 1997, Nature.

[58]  D. Clapham,et al.  G PROTEIN BETA GAMMA SUBUNITS , 1997 .

[59]  H. Hamm,et al.  Mapping of Effector Binding Sites of Transducin α-Subunit Using Gαt/Gαil Chimeras (*) , 1996, The Journal of Biological Chemistry.

[60]  H. Hamm,et al.  Potent Peptide Analogues of a G Protein Receptor-binding Region Obtained with a Combinatorial Library (*) , 1996, The Journal of Biological Chemistry.

[61]  Olivier Lichtarge,et al.  Receptor and βγ Binding Sites in the α Subunit of the Retinal G Protein Transducin , 1997, Science.

[62]  G. Schultz,et al.  Selectivity in signal transduction determined by gamma subunits of heterotrimeric G proteins. , 1993, Science.

[63]  J. Nyborg,et al.  The GTP binding motif: variations on a theme , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[64]  R. Iyengar,et al.  A surface on the G protein beta-subunit involved in interactions with adenylyl cyclases. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[65]  C. Downes,et al.  Purification and Characterization of Gβγ-responsive Phosphoinositide 3-Kinases from Pig Platelet Cytosol* , 1997, The Journal of Biological Chemistry.

[66]  W. Simonds,et al.  Selective Activation of Effector Pathways by Brain-specific G Protein β5* , 1996, The Journal of Biological Chemistry.

[67]  M. Resh.  Regulation of cellular signalling by fatty acid acylation and prenylation of signal transduction proteins. , 1996, Cellular signalling.

[68]  D. Barber,et al.  G13 Stimulates Na-H Exchange through Distinct Cdc42-dependent and RhoA-dependent Pathways (*) , 1996, The Journal of Biological Chemistry.

[69]  Y. Jan,et al.  Receptor-regulated ion channels. , 1997, Current opinion in cell biology.

[70]  J. Hescheler,et al.  G protein interaction with K+ and Ca2+ channels. , 1997, Trends in pharmacological sciences.

[71]  S. Volinia,et al.  Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. , 1995, Science.

[72]  J. Exton,et al.  Identification of Determinants in the -Subunit of G Required for Phospholipase C Activation (*) , 1996, The Journal of Biological Chemistry.

[73]  G. Schultz,et al.  A heterotrimeric G protein complex couples the muscarinic m1 receptor to phospholipase C-beta. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Emiko Suzuki,et al.  A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade , 1997, Nature.

[75]  J. Wess,et al.  Molecular basis of receptor/G protein coupling selectivity studied by coexpression of wild type and mutant m2 muscarinic receptors with mutant G alpha(q) subunits. , 1997, Biochemistry.

[76]  J. Thorner,et al.  Ste5 RING-H2 domain: role in Ste4-promoted oligomerization for yeast pheromone signaling. , 1997, Science.

[77]  K. Yan,et al.  Structural Determinants for Interaction with Three Different Effectors on the G Protein β Subunit* , 1997, The Journal of Biological Chemistry.

[78]  S. Sprang,et al.  The structure of the G protein heterotrimer Giα1 β 1 γ 2 , 1995, Cell.

[79]  F E Cohen,et al.  Evolutionarily conserved Galphabetagamma binding surfaces support a model of the G protein-receptor complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Heidi E. Hamm,et al.  The 2.2 Å crystal structure of transducin-α complexed with GTPγS , 1993, Nature.