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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 11, 2005; DOI: 10.1124/jpet.104.079954

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Received for publication November 4, 2004.
Revised January 20, 2005.
Accepted for publication March 8, 2005.

Neurokinin-1 receptor resensitization precedes receptor recycling

Vicki J Bennett 1, Shane A Perrine 2, Mark Simmons 3*

1 West Virginia University School of Medicine 2 Temple University School of Medicine 3 NEOUCOM

* Address correspondence to: E-mail: simmons{at}neoucom.edu

Abstract

Following agonist binding, neurokinin-1 receptors undergo rapid desensitization followed by internalization and recycling. Desensitization requires receptor phosphorylation but does not require internalization, while resensitization is thought to require internalization and recycling. Our previous data, however, have suggested that, following activation and desensitization, 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, while 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 non-functional neurokinin-1 receptors to functional receptors at the plasma membrane.


Key words: desensitization, internalization, neurokinin-1 receptor, recycling, resensitization, substance P


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Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin
J. Physiol., November 1, 2005; 568(3): 1047 - 1056.
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