![[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. 52, Issue 6, 1087-1094, 1997
Department of Biochemistry and Biophysics (W.K.V., D.M.S., M.I.S.)
and
Environmental Health Sciences Center (M.I.S.), Oregon State
University, Corvallis, Oregon 97331-7305
The first step in the transmembrane signal mediated by G
protein-coupled receptors is binding of agonist to receptors at the cell surface. The mechanism of the resulting receptor activation is not
clear, but models based on the ternary complex model are capable of
explaining most of the observations that have been reported in G
protein-coupled receptors. This model suggests that a single
agonist/receptor/G protein complex capable of activating G protein is
formed as the result of agonist binding. Extensions of this basic model
differ primarily in whether an equilibrium between active and inactive
conformations is required to explain experimental results. We report
results on ligand binding and coupling to physiological effector
systems of the m2 muscarinic acetylcholine receptor site-directed
mutant Y403F (residue 403 mutated from tyrosine to phenylalanine)
expressed in Chinese hamster ovary cells and compare our results with
results reported for the homologous Y506F mutation in the m3 muscarinic
receptor [J. Biol. Chem. 267:19313-19319
(1992)]. The mutation in the m2 muscarinic receptor reduced absolute
agonist affinities more dramatically than in the m3 muscarinic
receptor. Unlike the results reported for the m3 subtype mutant, in
which coupling to physiological effector systems was reduced, coupling
to effector systems for the mutant in the m2 subtype was robust. In the
Y403F m2 muscarinic receptor, the difference between the two agonist
binding affinities was greater than in the wild-type receptor, whereas
in the m3 subtype, the effect of the mutation was to decrease this
difference. A prediction of the ternary complex model is that relative
binding affinities will affect the steady state concentration of the
agonist/receptor/G protein complex and, as the result, the extent of G
protein coupling. These results can best be rationalized by this model,
which suggests that the activation of G protein-coupled receptors is
achieved by the relative affinity of agonist for two receptor states
and does not require the existence of multiple states in conformational equilibrium.
This article has been cited by other articles:
|
|
 |
|
  R. V. Iancu, S. W. Jones, and R. D. Harvey Compartmentation of cAMP Signaling in Cardiac Myocytes: A Computational Study Biophys. J., May 1, 2007; 92(9): 3317 - 3331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Luo, H. R. Kranzler, L. Zuo, S. Wang, H. P. Blumberg, and J. Gelernter CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case-control structured association study Hum. Mol. Genet., August 15, 2005; 14(16): 2421 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Wang, A. L. Hinrichs, H. Stock, J. Budde, R. Allen, S. Bertelsen, J. M. Kwon, W. Wu, D. M. Dick, J. Rice, et al. Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome Hum. Mol. Genet., September 1, 2004; 13(17): 1903 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Voigtlander, K. Johren, M. Mohr, A. Raasch, C. Trankle, S. Buller, J. Ellis, H.-D. Holtje, and K. Mohr Allosteric Site on Muscarinic Acetylcholine Receptors: Identification of Two Amino Acids in the Muscarinic M2 Receptor That Account Entirely for the M2/M5 Subtype Selectivities of Some Structurally Diverse Allosteric Ligands in N-Methylscopolamine-Occupied Receptors Mol. Pharmacol., July 1, 2003; 64(1): 21 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Furukawa, T. Hamada, M. K. Hayashi, T. Haga, Y. Muto, H. Hirota, S. Yokoyama, K. Nagasawa, and M. Ishiguro Conformation of Ligands Bound to the Muscarinic Acetylcholine Receptor Mol. Pharmacol., October 1, 2002; 62(4): 778 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zahn, N. Eckstein, C. Trankle, W. Sadee, and K. Mohr Allosteric Modulation of Muscarinic Receptor Signaling: Alcuronium-Induced Conversion of Pilocarpine from an Agonist into an Antagonist J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 720 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Stengel and M. L. Cohen Low-Affinity M2 Receptor Binding State Mediates Mouse Atrial Bradycardia: Comparative Effects of Carbamylcholine and the M1 Receptor Agonists Sabcomeline and Xanomeline J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 818 - 824. [Abstract] [Full Text]
|
|
|
|
|
|
S. D. C. Ward, C. A. M. Curtis, and E. C. Hulme Alanine-Scanning Mutagenesis of Transmembrane Domain 6 of the M1 Muscarinic Acetylcholine Receptor Suggests that Tyr381 Plays Key Roles in Receptor Function Mol. Pharmacol., November 1, 1999; 56(5): 1031 - 1041. [Abstract] [Full Text]
|
|
|
|
|
|
X.-P. Huang, F. E. Williams, S. M. Peseckis, and W. S. Messer Jr. Pharmacological Characterization of Human m1 Muscarinic Acetylcholine Receptors with Double Mutations at the Junction of TM VI and the Third Extracellular Domain J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1129 - 1139. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Tokita, S. J. Hocart, T. Katsuno, S. A. Mantey, D. H. Coy, and R. T. Jensen Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368 J. Biol. Chem., January 5, 2001; 276(1): 495 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Mosser, I. J. Amana, and M. I. Schimerlik Kinetic Analysis of M2 Muscarinic Receptor Activation of Gi in Sf9 Insect Cell Membranes J. Biol. Chem., January 4, 2002; 277(2): 922 - 931. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
