![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 294, Issue 2, 407-412, August 2000
Department of Pharmacology, School of Medicine, University of
California, San Diego, La Jolla, California (R.S.O., P.A.I.); and
Division of Cardiovascular Medicine, Gill Heart Institute, University
of Kentucky, Lexington, Kentucky (S.R.P.)
There is great therapeutic interest in manipulating (either enhancing
or suppressing) G protein-coupled receptor (GPCR) signal transduction.
However, most current strategies are limited to pharmacological
activation or blockade of receptors. Human gene therapy, including both
overexpression and antisense approaches, may allow manipulation of GPCR
signaling at steps distal to receptors. To fully understand the impact
of such therapy, the transduction of signals between the multiple
components of GPCR signaling and their interaction with other cellular
molecules must be understood in the context of both normal physiology
and disease. Defining the stoichiometric relationship among multiple
components of GPCR signaling is a first step. We summarize data showing
the substantial excess of G
s relative to
both 
-adrenergic receptors and adenylyl cyclase. A predominant idea
regarding signaling via GPCRs has for over 20 years emphasized the
concept of random movement and collision ("collision coupling") of
proteins within the lipid bilayer of the plasma membrane. This notion
does not readily account for the rapidity and fidelity of signal
transduction by the multiple components involved in GPCR-G
protein-effector systems, especially considering the low abundance of
these proteins in cells. Recently, many components involved in signal
transduction by GPCRs have been shown to exist primarily in
microdomains of the plasma membrane, in particular, caveolae. These and
other structures may serve to compartmentalize signals, thereby
optimizing signal transduction between an agonist and specific
effectors. The formation, organization, and maintenance of such
structures may prove to be altered in disease states associated with
disregulated signaling. In addition, we speculate that identification
of genetic polymorphisms of and therapy targeted to components that are
critical for determining efficacy (e.g., effectors such as adenylyl
cyclase) will provide important future therapeutic strategies.
This article has been cited by other articles:
|
|
 |
|
  S. M. Pontier, Y. Percherancier, S. Galandrin, A. Breit, C. Gales, and M. Bouvier Cholesterol-dependent Separation of the {beta}2-Adrenergic Receptor from Its Partners Determines Signaling Efficacy: INSIGHT INTO NANOSCALE ORGANIZATION OF SIGNAL TRANSDUCTION J. Biol. Chem., September 5, 2008; 283(36): 24659 - 24672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Qin, P. R. Sethi, and N. A. Lambert Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins FASEB J, August 1, 2008; 22(8): 2920 - 2927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Renner, K. Glebov, T. Lang, E. Papusheva, S. Balakrishnan, B. Keller, D. W. Richter, R. Jahn, and E. Ponimaskin Localization of the Mouse 5-Hydroxytryptamine1A Receptor in Lipid Microdomains Depends on Its Palmitoylation and Is Involved in Receptor-Mediated Signaling Mol. Pharmacol., September 1, 2007; 72(3): 502 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Griffin, K. W. Figueroa, S. Liller, and F. J. Ehlert Estimation of Agonist Activity at G Protein-Coupled Receptors: Analysis of M2 Muscarinic Receptor Signaling through Gi/o,Gs, and G15 J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1193 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Bundey and P. A. Insel Adenylyl Cyclase 6 Overexpression Decreases the Permeability of Endothelial Monolayers via Preferential Enhancement of Prostacyclin Receptor Function Mol. Pharmacol., November 1, 2006; 70(5): 1700 - 1707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Patel, B. P. Head, H. N. Petersen, I. R. Niesman, D. Huang, G. J. Gross, P. A. Insel, and D. M. Roth Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and {delta}-opioid receptors Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H344 - H350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Krumins and A. G. Gilman Targeted Knockdown of G Protein Subunits Selectively Prevents Receptor-mediated Modulation of Effectors and Reveals Complex Changes in Non-targeted Signaling Proteins J. Biol. Chem., April 14, 2006; 281(15): 10250 - 10262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. L. Smith, Y. Lei, J. Liu, M. E. Cahill, G. M. Hagen, B. G. Barisas, and D. A. Roess Luteinizing Hormone Receptors Translocate to Plasma Membrane Microdomains after Binding of Human Chorionic Gonadotropin Endocrinology, April 1, 2006; 147(4): 1789 - 1795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Head, H. H. Patel, D. M. Roth, N. C. Lai, I. R. Niesman, M. G. Farquhar, and P. A. Insel G-protein-coupled Receptor Signaling Components Localize in Both Sarcolemmal and Intracellular Caveolin-3-associated Microdomains in Adult Cardiac Myocytes J. Biol. Chem., September 2, 2005; 280(35): 31036 - 31044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wieland and M. C. Michel Can a GDP-Liganded G-Protein Be Active? Mol. Pharmacol., September 1, 2005; 68(3): 559 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Maudsley, B. Martin, and L. M. Luttrell The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 485 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Rudajev, J. Novotny, L. Hejnova, G. Milligan, and P. Svoboda Dominant Portion of Thyrotropin-Releasing Hormone Receptor Is Excluded from Lipid Domains. Detergent-Resistant and Detergent-Sensitive Pools of TRH Receptor and Gq{alpha}/G11{alpha} Protein J. Biochem., August 1, 2005; 138(2): 111 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lagane, S. Ballet, T. Planchenault, K. Balabanian, E. Le Poul, C. Blanpain, Y. Percherancier, I. Staropoli, G. Vassart, M. Oppermann, et al. Mutation of the DRY Motif Reveals Different Structural Requirements for the CC Chemokine Receptor 5-Mediated Signaling and Receptor Endocytosis Mol. Pharmacol., June 1, 2005; 67(6): 1966 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Bornheimer, M. R. Maurya, M. G. Farquhar, and S. Subramaniam Computational modeling reveals how interplay between components of a GTPase-cycle module regulates signal transduction PNAS, November 9, 2004; 101(45): 15899 - 15904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Trivedi, V. A. Narkar, T. Hussain, and M. F. Lokhandwala Dopamine recruits D1A receptors to Na-K-ATPase-rich caveolar plasma membranes in rat renal proximal tubules Am J Physiol Renal Physiol, November 1, 2004; 287(5): F921 - F931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ostrom, R. A. Bundey, and P. A. Insel Nitric Oxide Inhibition of Adenylyl Cyclase Type 6 Activity Is Dependent upon Lipid Rafts and Caveolin Signaling Complexes J. Biol. Chem., May 7, 2004; 279(19): 19846 - 19853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Bundey and P. A. Insel Discrete Intracellular Signaling Domains of Soluble Adenylyl Cyclase: Camps of cAMP? Sci. Signal., May 4, 2004; 2004(231): pe19 - pe19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, R. S. Ostrom, and P. A. Insel cAMP-elevating agents and adenylyl cyclase overexpression promote an antifibrotic phenotype in pulmonary fibroblasts Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1089 - C1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Little, M. E. Hemler, and C. S. Stipp Dynamic Regulation of a GPCR-Tetraspanin-G Protein Complex on Intact Cells: Central Role of CD81 in Facilitating GPR56-G{alpha}q/11 Association Mol. Biol. Cell, May 1, 2004; 15(5): 2375 - 2387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kirstein and P. A. Insel Autonomic Nervous System Pharmacogenomics: A Progress Report Pharmacol. Rev., March 1, 2004; 56(1): 31 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Agnati, S. Ferre, C. Lluis, R. Franco, and K. Fuxe Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons Pharmacol. Rev., September 1, 2003; 55(3): 509 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Seifert, K. Wenzel-Seifert, T. Burckstummer, H. H. Pertz, W. Schunack, S. Dove, A. Buschauer, and S. Elz Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1104 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nanjundan and F. Possmayer Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L1 - L23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Daumas, N. Destainville, C. Millot, A. Lopez, D. Dean, and L. Salome Confined Diffusion Without Fences of a G-Protein-Coupled Receptor as Revealed by Single Particle Tracking Biophys. J., January 1, 2003; 84(1): 356 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ostrom, X. Liu, B. P. Head, C. Gregorian, T. M. Seasholtz, and P. A. Insel Localization of Adenylyl Cyclase Isoforms and G Protein-Coupled Receptors in Vascular Smooth Muscle Cells: Expression in Caveolin-Rich and Noncaveolin Domains Mol. Pharmacol., November 1, 2002; 62(5): 983 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xiang, E. Devic, and B. Kobilka The PDZ Binding Motif of the beta 1 Adrenergic Receptor Modulates Receptor Trafficking and Signaling in Cardiac Myocytes J. Biol. Chem., September 6, 2002; 277(37): 33783 - 33790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Quillan, K. W. Carlson, C. Song, D. Wang, and W. Sadee Differential Effects of {micro}-Opioid Receptor Ligands on Ca2+ Signaling J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 1002 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Razani, S. E. Woodman, and M. P. Lisanti Caveolae: From Cell Biology to Animal Physiology Pharmacol. Rev., September 1, 2002; 54(3): 431 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Huang, X. Song, H.-Y. Wang, and C. C. Malbon Targeted expression of activated Q227L Galpha s in vivo Am J Physiol Cell Physiol, August 1, 2002; 283(2): C386 - C395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Dumont, S. Dremier, I. Pirson, and C. Maenhaut Cross signaling, cell specificity, and physiology Am J Physiol Cell Physiol, July 1, 2002; 283(1): C2 - C28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Berlot A Highly Effective Dominant Negative alpha s Construct Containing Mutations That Affect Distinct Functions Inhibits Multiple Gs-coupled Receptor Signaling Pathways J. Biol. Chem., May 31, 2002; 277(23): 21080 - 21085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Stitham, A. Stojanovic, and J. Hwa Impaired Receptor Binding and Activation Associated with a Human Prostacyclin Receptor Polymorphism J. Biol. Chem., May 3, 2002; 277(18): 15439 - 15444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ryden, G. Faulds, J. Hoffstedt, A. Wennlund, and P. Arner Effect of the (C825T) G{beta}3 Polymorphism on Adrenoceptor-Mediated Lipolysis in Human Fat Cells Diabetes, May 1, 2002; 51(5): 1601 - 1608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Stitham, K. A. Martin, and J. Hwa The Critical Role of Transmembrane Prolines in Human Prostacyclin Receptor Activation Mol. Pharmacol., May 1, 2002; 61(5): 1202 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S Ostrom New Determinants of Receptor-Effector Coupling: Trafficking and Compartmentation in Membrane Microdomains Mol. Pharmacol., March 1, 2002; 61(3): 473 - 476. [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ostrom, C. Gregorian, R. M. Drenan, Y. Xiang, J. W. Regan, and P. A. Insel Receptor Number and Caveolar Co-localization Determine Receptor Coupling Efficiency to Adenylyl Cyclase J. Biol. Chem., November 2, 2001; 276(45): 42063 - 42069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Eckhart and W. J. Koch Transgenic Studies of Cardiac Adrenergic Receptor Regulation J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 1 - 5. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Imai, B. Jiang, and A. J Pappano Mechanism for muscarinic inhibition of ICa(L) is determined by the path for elevating cyclic AMP in cardiac myocytes Cardiovasc Res, August 1, 2001; 51(2): 331 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Stevens, J. Pediani, J. J. Carrillo, and G. Milligan Coordinated Agonist Regulation of Receptor and G Protein Palmitoylation and Functional Rescue of Palmitoylation-deficient Mutants of the G Protein G11alpha following Fusion to the alpha 1b-Adrenoreceptor. PALMITOYLATION OF G11alpha IS NOT REQUIRED FOR INTERACTION WITH beta {middle dot}gamma COMPLEX J. Biol. Chem., September 14, 2001; 276(38): 35883 - 35890. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
