| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 268, Issue 30, 22273-22276, 10, 1993
O Moro, J Lameh, P Hogger and W Sadee
Signal transduction of the heptahelical G protein-coupled receptors (GPCRs)
involves multiple receptor domains, but a universal consensus domain for
coupling has not yet been defined. Alanine mutagenesis scanning was
performed on the intracellular loops and the COOH tail of the human
muscarinic cholinergic receptor (Hm1) to identify coupling domains.
Stimulation of phosphatidylinositol (PI) turnover was determined after
transfection of the alanine mutants into U293 human embryonic kidney cells.
Alanine substitutions in four regions (loops i1, i2, and NH2 and COOH
junctions of i3) impaired coupling efficiency by approximately 50% or more,
but the strongest reduction (> 80%) resulted from alanine replacement of
a single amino acid, leucine 131. This residue is located in the middle of
the second intracellular loop (i2), within the highly conserved GPCR motif
(DRYXXV(I)XXPL). The position equivalent to Leu-131 in Hm1 contains a bulky
hydrophobic amino acid (L, I, V, M, or F) in nearly all cloned GPCRs.
Substitution of Leu-131 with polar amino acids (aspartate and asparagine)
also resulted in strongly defective coupling, whereas phenylalanine (found
in the equivalent position in the beta 2 adrenoceptor) can replace leucine
without losing PI coupling ability of Hm1. Alanine substitution of the
corresponding amino acid in the Hm3 receptor (L174A) also inhibited
agonist-stimulated PI turnover, while replacing Phe-139 with alanine in the
beta 2 adrenoceptor suppressed stimulation of adenylyl cyclase. We propose
that a bulky hydrophobic amino acid in the middle of the i2 loop serves as
a general site relevant to G protein coupling, whereas coupling selectivity
is governed by other receptor domains.
Hydrophobic amino acid in the i2 loop plays a key role in receptor-G protein coupling
Department of Pharmacy, University of California, San Francisco 94143- 0446.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  R. T. Jensen, J. F. Battey, E. R. Spindel, and R. V. Benya International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States Pharmacol. Rev., March 1, 2008; 60(1): 1 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Berg, J. Dunlop, T. Sanchez, M. Silva, and W. P. Clarke A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin2C Receptor Alters Both Ligand-Dependent and -Independent Receptor Signaling J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1084 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Rovati, V. Capra, and R. R. Neubig The Highly Conserved DRY Motif of Class A G Protein-Coupled Receptors: Beyond the Ground State Mol. Pharmacol., April 1, 2007; 71(4): 959 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Matsumoto, K. Narzinski, P. D. Kiser, G. V. Nikiforovich, and T. J. Baranski A Comprehensive Structure-Function Map of the Intracellular Surface of the Human C5a Receptor: I. IDENTIFICATION OF CRITICAL RESIDUES J. Biol. Chem., February 2, 2007; 282(5): 3105 - 3121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Abbracchio, G. Burnstock, J.-M. Boeynaems, E. A. Barnard, J. L. Boyer, C. Kennedy, G. E. Knight, M. Fumagalli, C. Gachet, K. A. Jacobson, et al. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy Pharmacol. Rev., September 1, 2006; 58(3): 281 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marion, R. H. Oakley, K.-M. Kim, M. G. Caron, and L. S. Barak A beta-Arrestin Binding Determinant Common to the Second Intracellular Loops of Rhodopsin Family G Protein-coupled Receptors J. Biol. Chem., February 3, 2006; 281(5): 2932 - 2938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Saito, M. Tetsuka, S. Saito, K. Imai, A. Yoshikawa, H. Doi, and K. Maruyama Arginine Residue 155 in the Second Intracellular Loop Plays a Critical Role in Rat Melanin-Concentrating Hormone Receptor 1 Activation Endocrinology, August 1, 2005; 146(8): 3452 - 3462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Laghmani, A. Sakamoto, M. Yanagisawa, P. A. Preisig, and R. J. Alpern A consensus sequence in the endothelin-B receptor second intracellular loop is required for NHE3 activation by endothelin-1 Am J Physiol Renal Physiol, April 1, 2005; 288(4): F732 - F739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baurand, A. Eckly, B. Hechler, G. Kauffenstein, J.-L. Galzi, J.-P. Cazenave, C. Leon, and C. Gachet Differential Regulation and Relocalization of the Platelet P2Y Receptors after Activation: A Way to Avoid Loss of Hemostatic Properties? Mol. Pharmacol., March 1, 2005; 67(3): 721 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Capra, A. Veltri, C. Foglia, L. Crimaldi, A. Habib, M. Parenti, and G. E. Rovati Mutational Analysis of the Highly Conserved ERY Motif of the Thromboxane A2 Receptor: Alternative Role in G Protein-Coupled Receptor Signaling Mol. Pharmacol., October 1, 2004; 66(4): 880 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Tao and D. L. Segaloff Functional Characterization of Melanocortin-3 Receptor Variants Identify a Loss-of-Function Mutation Involving an Amino Acid Critical for G Protein-Coupled Receptor Activation J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3936 - 3942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sugimoto, T. Nakato, A. Kita, Y. Takahashi, N. Hatae, H. Tabata, S. Tanaka, and A. Ichikawa A Cluster of Aromatic Amino Acids in the i2 Loop Plays a Key Role for Gs Coupling in Prostaglandin EP2 and EP3 Receptors J. Biol. Chem., March 19, 2004; 279(12): 11016 - 11026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schumann, T. Nakagawa, S. A. Mantey, K. Tokita, D. J. Venzon, S. J. Hocart, R. V. Benya, and R. T. Jensen Importance of Amino Acids of the Central Portion of the Second Intracellular Loop of the Gastrin-Releasing Peptide Receptor for Phospholipase C Activation, Internalization, and Chronic Down-Regulation J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 597 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gaborik, G. Jagadeesh, M. Zhang, A. Spat, K. J. Catt, and L. Hunyady The Role of a Conserved Region of the Second Intracellular Loop in AT1 Angiotensin Receptor Activation and Signaling Endocrinology, June 1, 2003; 144(6): 2220 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-Y. Lin, M. G. Varma, A. Joubel, S. Madabushi, O. Lichtarge, and D. L. Barber Conserved Motifs in Somatostatin, D2-dopamine, and alpha 2B-Adrenergic Receptors for Inhibiting the Na-H Exchanger, NHE1 J. Biol. Chem., April 18, 2003; 278(17): 15128 - 15135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Greasley, F. Fanelli, A. Scheer, L. Abuin, M. Nenniger-Tosato, P. G. DeBenedetti, and S. Cotecchia Mutational and Computational Analysis of the alpha 1b-Adrenergic Receptor. INVOLVEMENT OF BASIC AND HYDROPHOBIC RESIDUES IN RECEPTOR ACTIVATION AND G PROTEIN COUPLING J. Biol. Chem., November 30, 2001; 276(49): 46485 - 46494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Visiers, S. A. Hassan, and H. Weinstein Differences in conformational properties of the second intracellular loop (IL2) in 5HT2C receptors modified by RNA editing can account for G protein coupling efficiency Protein Eng. Des. Sel., June 1, 2001; 14(6): 409 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Alewijnse, H. Timmerman, E. H. Jacobs, M. J. Smit, E. Roovers, S. Cotecchia, and R. Leurs The Effect of Mutations in the DRY Motif on the Constitutive Activity and Structural Instability of the Histamine H2 Receptor Mol. Pharmacol., May 1, 2000; 57(5): 890 - 898. [Abstract] [Full Text]
|
|
|
|
|
|
H.-O. Chung, Q. Yang, K. J. Catt, and K. K. Arora Expression and Function of the Gonadotropin-releasing Hormone Receptor Are Dependent on a Conserved Apolar Amino Acid in the Third Intracellular Loop J. Biol. Chem., December 10, 1999; 274(50): 35756 - 35762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Miettinen, J. M. Gripentrog, M. M. Mason, and A. J. Jesaitis Identification of Putative Sites of Interaction between the Human Formyl Peptide Receptor and G Protein J. Biol. Chem., September 24, 1999; 274(39): 27934 - 27942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Niswender, S. C. Copeland, K. Herrick-Davis, R. B. Emeson, and E. Sanders-Bush RNA Editing of the Human Serotonin 5-Hydroxytryptamine 2C Receptor Silences Constitutive Activity J. Biol. Chem., April 2, 1999; 274(14): 9472 - 9478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. NISWENDER, E. SANDERS-BUSH, and R. B. EMESON Identification and Characterization of RNA Editing Events within the 5-HT2C Receptor Ann. N.Y. Acad. Sci., December 15, 1998; 861(1): 38 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. ALBERT, S. J. MORRIS, M. H. GHAHREMANI, J. M. STORRING, and P. M. C. LEMBO A Putative {alpha}-helical G{beta}{gamma}-coupling Domain in the Second Intracellular Loop of the 5-HT1A Receptor Ann. N.Y. Acad. Sci., December 15, 1998; 861(1): 146 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. N. Prado, D. F. Mierke, M. Pellegrini, L. Taylor, and P. Polgar Motif Mutation of Bradykinin B2 Receptor Second Intracellular Loop and Proximal C Terminus Is Critical for Signal Transduction, Internalization, and Resensitization J. Biol. Chem., December 11, 1998; 273(50): 33548 - 33555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Burstein, T. A. Spalding, and M. R. Brann The Second Intracellular Loop of the m5 Muscarinic Receptor Is the Switch Which Enables G-protein Coupling J. Biol. Chem., September 18, 1998; 273(38): 24322 - 24327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ulloa-Aguirre, D. Stanislaus, V. Arora, J. Vaananen, S. Brothers, J. A. Janovick, and P. M. Conn The Third Intracellular Loop of the Rat Gonadotropin-Releasing Hormone Receptor Couples the Receptor to Gs- and Gq/11-Mediated Signal Transduction Pathways: Evidence from Loop Fragment Transfection in GGH3 Cells Endocrinology, May 1, 1998; 139(5): 2472 - 2478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Thompson, S. M. Wade, J. K. Harrison, M. N. Salafranca, and R. R. Neubig Cotransfection of Second and Third Intracellular Loop Fragments Inhibit Angiotensin AT1a Receptor Activation of Phospholipase C in HEK-293 Cells J. Pharmacol. Exp. Ther., April 1, 1998; 285(1): 216 - 222. [Abstract] [Full Text]
|
|
|
|
|
|
P. M. C. Lembo, M. H. Ghahremani, S. J. Morris, and P. R. Albert A Conserved Threonine Residue in the Second Intracellular Loop of the 5-Hydroxytryptamine 1A Receptor Directs Signaling Specificity Mol. Pharmacol., July 1, 1997; 52(1): 164 - 171. [Abstract] [Full Text]
|
|
|
|
|
|
M. Farzan, H. Choe, K. A. Martin, Y. Sun, M. Sidelko, C. R. Mackay, N. P. Gerard, J. Sodroski, and C. Gerard HIV-1 Entry and Macrophage Inflammatory Protein-1beta -mediated Signaling Are Independent Functions of the Chemokine Receptor CCR5 J. Biol. Chem., March 14, 1997; 272(11): 6854 - 6857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iida-Klein, J. Guo, M. Takemura, M. T. Drake, J. T. Potts Jr., A. Abou-Samra, F. R. Bringhurst, and G. V. Segre Mutations in the Second Cytoplasmic Loop of the Rat Parathyroid Hormone (PTH)/PTH-related Protein Receptor Result in Selective Loss of PTH-stimulated Phospholipase C Activity J. Biol. Chem., March 14, 1997; 272(11): 6882 - 6889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L.S. Milne, M. J. Caterina, and P. N. Devreotes Random Mutagenesis of the cAMP Chemoattractant Receptor, cAR1, of Dictyostelium. EVIDENCE FOR MULTIPLE STATES OF ACTIVATION J. Biol. Chem., January 24, 1997; 272(4): 2069 - 2076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Olah and M. E. Olah Identification of A2a Adenosine Receptor Domains Involved in Selective Coupling to GS. ANALYSIS OF CHIMERIC A1/A2a ADENOSINE RECEPTORS J. Biol. Chem., January 3, 1997; 272(1): 337 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-J. Lee, M. Evans, and T. Hla The Inducible G Protein-coupled Receptor edg-1 Signals via the G(i)/Mitogen-activated Protein Kinase Pathway J. Biol. Chem., May 10, 1996; 271(19): 11272 - 11279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Jockers, A. D. Silva, A. D. Strosberg, M. Bouvier, and S. Marullo New Molecular and Structural Determinants Involved in beta(2)-Adrenergic Receptor Desensitization and Sequestration J. Biol. Chem., April 19, 1996; 271(16): 9355 - 9362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smit, E. Roovers, H. Timmerman, Y. van de Vrede, A. E. Alewijnse, and R. Leurs Two Distinct Pathways for Histamine H(2) Receptor Down-regulation J. Biol. Chem., March 29, 1996; 271(13): 7574 - 7582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Martin, S. Rens-Domiano, P. J. Schatz, and H. E. Hamm Potent Peptide Analogues of a G Protein Receptor-binding Region Obtained with a Combinatorial Library J. Biol. Chem., January 5, 1996; 271(1): 361 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. T. Amatruda III, S. Dragas-Graonic, R. Holmes, and H. D. Perez Signal Transduction by the Formyl Peptide Receptor J. Biol. Chem., November 24, 1995; 270(47): 28010 - 28013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Arora, A. Sakai, and K. J. Catt Effects of Second Intracellular Loop Mutations on Signal Transduction and Internalization of the Gonadotropin-releasing Hormone Receptor J. Biol. Chem., September 29, 1995; 270(39): 22820 - 22826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Blin, J. Yun, and J. Wess Mapping of Single Amino Acid Residues Required for Selective Activation of G[IMAGE] by the m3 Muscarinic Acetylcholine Receptor J. Biol. Chem., July 28, 1995; 270(30): 17741 - 17748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Schneberg, J. Liu, and J. Wess Plasma Membrane Localization and Functional Rescue of Truncated Forms of a G Protein-coupled Receptor J. Biol. Chem., July 28, 1995; 270(30): 18000 - 18006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. P. Ernst, K. P. Hofmann, and T. P. Sakmar Characterization of Rhodopsin Mutants That Bind Transducin but Fail to Induce GTP Nucleotide Uptake J. Biol. Chem., May 5, 1995; 270(18): 10580 - 10586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Caterina, P. N. Devreotes, J. Borleis, and D. Hereld Agonist-induced Loss of Ligand Binding Is Correlated with Phosphorylation of cAR1, a G Protein-coupled Chemoattractant Receptor from Dictyostelium J. Biol. Chem., April 14, 1995; 270(15): 8667 - 8672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Högger, M. S. Shockley, J. Lameh, and W. Sadée Activating and Inactivating Mutations in N- and C-terminal i3 Loop Junctions of Muscarinic Acetylcholine Hm1 Receptors J. Biol. Chem., March 31, 1995; 270(13): 7405 - 7410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Caterina, D. Hereld, and P. N. Devreotes Occupancy of the Dictyostelium cAMP Receptor, cAR1, Induces a Reduction in Affinity Which Depends upon COOH-terminal Serine Residues J. Biol. Chem., March 3, 1995; 270(9): 4418 - 4423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shi, S. Osawa, C. D. Dickerson, and E. R. Weiss Rhodopsin Mutants Discriminate Sites Important for the Activation of Rhodopsin Kinase and G(t) J. Biol. Chem., February 3, 1995; 270(5): 2112 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Erlenbach, E. Kostenis, C. Schmidt, C. S.-L. Gal, D. Raufaste, M. E. Dumont, M. H. Pausch, and J. Wess Single Amino Acid Substitutions and Deletions That Alter the G Protein Coupling Properties of the V2 Vasopressin Receptor Identified in Yeast by Receptor Random Mutagenesis J. Biol. Chem., July 27, 2001; 276(31): 29382 - 29392. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
