QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.079954v1 313/3/1347    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bennett, V. J. Articles by Simmons, M. A. Search for Related Content PubMed PubMed Citation Articles by Bennett, V. J. Articles by Simmons, M. A.

CELLULAR AND MOLECULAR

Neurokinin-1 Receptor Resensitization Precedes Receptor Recycling

Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; and Pharmacology Graduate Program, School of Biomedical Sciences, Kent State University, Kent, Ohio

Following agonist binding, neurokinin-1 receptors undergo rapid desensitization followed by internalization and recycling. Desensitization requires receptor phosphorylation but does not require internalization, whereas resensitization is thought to require internalization and recycling. Our previous data, however, have suggested that, following activation and desensitization, the return of responsiveness to the neurokinin-1 agonist substance P (termed "resensitization") occurs hours before internalized receptors are recycled back to the plasma membrane. To further investigate this novel mechanism of neurokinin-1 receptor resensitization, we have studied the time courses of neurokinin-1 receptor responsiveness, recycling, and dephosphorylation by measuring cellular Ca²⁺ responses, ligand-receptor binding, and receptor phosphorylation, respectively. Concentration-response curves and competition binding curves were obtained at various times following desensitization. The effects of the nonhydrolyzable GTP analog Gpp(NH)p on substance P binding were also studied to assess receptor-G protein coupling. After receptor activation and desensitization, Ca²⁺ signaling in response to substance P occurred within 90 min, whereas the return of receptor binding required 240 min. Receptor dephosphorylation was greater than 90% complete 20 min after agonist washout. In addition, the return of substance P responsiveness coincided with a return in sensitivity of substance P binding to Gpp(NH)p, indicating a return in receptor-G protein coupling. These data show that the resensitization of responsiveness to substance P precedes receptor recycling. This may result from a conversion of nonfunctional neurokinin-1 receptors to functional receptors at the plasma membrane.

Address correspondence to: Dr. Mark A. Simmons, NEOUCOM, 4209 St. Rt. 44, P.O. Box 95, Rootstown, OH 44272. E-mail: simmons{at}neoucom.edu

This article has been cited by other articles:

				B. J Wong, N. J Tublitz, and C. T Minson Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin J. Physiol., November 1, 2005; 568(3): 1047 - 1056. [Abstract] [Full Text] [PDF]