JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ford, D. J.
Right arrow Articles by Ellis, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ford, D. J.
Right arrow Articles by Ellis, J.

Vol. 300, Issue 3, 810-817, March 2002

Homologous Mutations Near the Junction of the Sixth Transmembrane Domain and the Third Extracellular Loop Lead to Constitutive Activity and Enhanced Agonist Affinity at all Muscarinic Receptor Subtypes

Diane J. Ford, Anthony Essex, Tracy A. Spalding, Ethan S. Burstein and John Ellis

Department of Pharmacology (D.J.F., J.E.) and Department of Psychiatry (J.E.), the Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and ACADIA Pharmaceuticals (A.E., T.A.S., E.S.B.), San Diego, California

Previous studies have found that a mutation near the junction of the sixth transmembrane domain (TM6) and the third extracellular loop of the M5 muscarinic receptor leads to constitutive activation and enhanced agonist affinity for the mutated receptor. These results were consistent with the extended ternary complex model, which predicts a correlation between agonist affinity and constitutive activity. We have introduced the homologous mutation into all five subtypes of the highly conserved muscarinic receptor family; SerThrright-arrowTyrPro was introduced into M1 and M5, and AsnThrright-arrowTyrPro was introduced into M2, M3, and M4. In binding assays, these mutations produced increases in affinities toward acetylcholine and carbachol that ranged from 5-fold at the M2 receptor to 15- to 20-fold at M1, M3, and M4, to 40-fold at M5. In functional assays, all five mutant receptors exhibited constitutive activity, at levels ranging between 30 and 80% of the maximal response elicited by carbachol. In every case, the muscarinic antagonist atropine inhibited this constitutive activity with high affinity. Thus, despite differences in effector coupling and in wild-type sequence at the mutation site, all five subtypes were activated by this mutation at the top of TM6. Previous studies of the M5 subtype have indicated that TM6 is a ligand-dependent switch that sets the activation state of the receptor. Based on the results of the present study, it is possible that TM6 represents a general switch for the activation of the muscarinic receptor family.

0022-3565/02/3003-0810$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
H. D. Lim, A. Jongejan, R. A. Bakker, E. Haaksma, I. J. P. de Esch, and R. Leurs
Phenylalanine 169 in the Second Extracellular Loop of the Human Histamine H4 Receptor Is Responsible for the Difference in Agonist Binding between Human and Mouse H4 Receptors
J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 88 - 96.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Zhuang and H. Matsunami
Synergism of Accessory Factors in Functional Expression of Mammalian Odorant Receptors
J. Biol. Chem., May 18, 2007; 282(20): 15284 - 15293.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. R. Dowling, J. M. Willets, D. C. Budd, S. J. Charlton, S. R. Nahorski, and R. A. J. Challiss
A Single Point Mutation (N514Y) in the Human M3 Muscarinic Acetylcholine Receptor Reveals Differences in the Properties of Antagonists: Evidence for Differential Inverse Agonism
J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1134 - 1142.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. P. Nelson, S. R. Nahorski, and R. A. J. Challiss
Constitutive Activity and Inverse Agonism at the M2 Muscarinic Acetylcholine Receptor
J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 279 - 288.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
X.-P. Huang, S. Prilla, K. Mohr, and J. Ellis
Critical Amino Acid Residues of the Common Allosteric Site on the M2 Muscarinic Acetylcholine Receptor: More Similarities than Differences between the Structurally Divergent Agents Gallamine and Bis(ammonio)alkane-Type Hexamethylene-bis-[dimethyl-(3-phthalimidopropyl)ammonium]dibromide
Mol. Pharmacol., September 1, 2005; 68(3): 769 - 778.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Tumova, R. M. Iwasiow, and M. Tiberi
Insight into the Mechanism of Dopamine D1-like Receptor Activation. EVIDENCE FOR A MOLECULAR INTERPLAY BETWEEN THE THIRD EXTRACELLULAR LOOP AND THE CYTOPLASMIC TAIL
J. Biol. Chem., February 28, 2003; 278(10): 8146 - 8153.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Cattaneo, M. L. Zighetti, R. Lombardi, C. Martinez, A. Lecchi, P. B. Conley, J. Ware, and Z. M. Ruggeri
Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding
PNAS, February 18, 2003; 100(4): 1978 - 1983.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.