MolPharm Over 1500 Individual Drug Articles!

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
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 He, M.-L.
Right arrow Articles by Stojilkovic, S. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by He, M.-L.
Right arrow Articles by Stojilkovic, S. S.

Vol. 62, Issue 5, 1187-1197, November 2002

Purinergic P2X2 Receptor Desensitization Depends on Coupling between Ectodomain and C-Terminal Domain

Mu-Lan He, Taka-aki Koshimizu,1 Melanija Tomic', and Stanko S. Stojilkovic

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

The wild-type P2X2 purinergic receptor (P2X2aR) and its splice form lacking the intracellular Val370-Gln438 C-terminal sequence (P2X2bR) respond to ATP stimulation with comparable EC50 values and peak current/calcium responses but desensitize in a receptor-specific manner. P2X2aR desensitizes slowly and P2X2bR desensitizes rapidly. We studied the effects of different agonists, and of substituting the ectodomain, on the pattern of calcium signaling by P2X2aR and P2X2bR. Both receptors showed similar EC50 values (estimated from the peak calcium response) and IC50 values (estimated from the rate of calcium signal desensitization) for agonists, in the order 2-MeS-ATP <=  ATP <=  ATPgamma S < BzATP alpha beta -meATP, and the IC50 values for agonists were shifted to the right compared with their EC50 values. Furthermore, the ATP-induced receptor-subtype specific pattern of desensitization was mimicked by high- but not by low-efficacy agonists, suggesting a ligand-specific desensitization pattern. To test this hypothesis, we generated chimeric P2X2aR and P2X2bR containing the Val60-Phe301 ectodomain sequence of P2X3R and Val61-Phe313 ectodomain sequence of P2X7R instead the native Ile66-Tyr310 sequence. The mutated P2X2a+X3R and P2X2b+X3R exhibited comparable EC50 values for ATP, BzATP, and alpha beta -meATP in the submicromolar concentration range and desensitized in a receptor-specific and ligand-nonspecific manner. On the other hand, the chimeric P2X2+X7R exhibited decreased sensitivity for ATP and desensitized in a receptor-nonspecific manner. These results suggest that efficacy of agonists for the ligand-binding domain of P2X2Rs reflects the strength of desensitization controlled by their C-terminal structures.

1 Current address: Department of Molecular Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.

Copyright © 2002 by U.S. Government


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
S. J. Fountain and R. A. North
A C-terminal Lysine That Controls Human P2X4 Receptor Desensitization
J. Biol. Chem., June 2, 2006; 281(22): 15044 - 15049.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Hausmann, J. Rettinger, Z. Gerevich, S. Meis, M. U. Kassack, P. Illes, G. Lambrecht, and G. Schmalzing
The Suramin Analog 4,4',4'',4'''-(Carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic Acid (NF110) Potently Blocks P2X3 Receptors: Subtype Selectivity Is Determined by Location of Sulfonic Acid Groups
Mol. Pharmacol., June 1, 2006; 69(6): 2058 - 2067.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
S. S. STOJILKOVIC, M. TOMIC, M.-L. HE, Z. YAN, T.-A. KOSHIMIZU, and H. ZEMKOVA
Molecular Dissection of Purinergic P2X Receptor Channels
Ann. N.Y. Acad. Sci., June 1, 2005; 1048(1): 116 - 130.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Fabbretti, E. Sokolova, L. Masten, M. D'Arco, A. Fabbro, A. Nistri, and R. Giniatullin
Identification of Negative Residues in the P2X3 ATP Receptor Ectodomain as Structural Determinants for Desensitization and the Ca2+-sensing Modulatory Sites
J. Biol. Chem., December 17, 2004; 279(51): 53109 - 53115.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M. Y. Kochukov and A. K. Ritchie
A P2X7 receptor stimulates plasma membrane trafficking in the FRTL rat thyrocyte cell line
Am J Physiol Cell Physiol, October 1, 2004; 287(4): C992 - C1002.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
H. Zemkova, M.-L. He, T.-a. Koshimizu, and S. S. Stojilkovic
Identification of Ectodomain Regions Contributing to Gating, Deactivation, and Resensitization of Purinergic P2X Receptors
J. Neurosci., August 4, 2004; 24(31): 6968 - 6978.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Rettinger and G. Schmalzing
Desensitization Masks Nanomolar Potency of ATP for the P2X1 Receptor
J. Biol. Chem., February 20, 2004; 279(8): 6426 - 6433.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M.-L. He, H. Zemkova, T.-a. Koshimizu, M. Tomic, and S. S. Stojilkovic
Intracellular calcium measurements as a method in studies on activity of purinergic P2X receptor channels
Am J Physiol Cell Physiol, August 1, 2003; 285(2): C467 - C479.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M.-L. He, H. Zemkova, and S. S. Stojilkovic
Dependence of Purinergic P2X Receptor Activity on Ectodomain Structure
J. Biol. Chem., March 14, 2003; 278(12): 10182 - 10188.
[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