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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 11, 2003; DOI: 10.1124/jpet.103.053082

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Received for publication April 24, 2003.
Revised June 3, 2003.
Accepted for publication July 30, 2003.

Neuropeptide Y Receptor-mediated Sensitization of ATP- stimulated Inositol Phosphate Formation

Desinee A. Drakulich 1, April M. Walls 1, Myron L. Toews 1, Terry D. Hexum 1*

1 University of Nebraska Medical Center

* Address correspondence to: E-mail: thexum{at}unmc.edu

Abstract

Activation of bovine chromaffin cell neuropeptide Y (NPY) receptors coupled to Gi (Y1) results in the enhancement of ATP-stimulated inositol phosphate formation. NPY alone does not alter inositol phosphate (InsP) formation in these cells suggesting that some form of receptor cross-talk is involved in this process. In some cell types, serial stimulation of Gi- linked and Gs- or Gq-linked receptors results in an increase in intracellular messenger production (cyclic AMP or InsP), a process referred to as heterologous sensitization. NPY preincubation with bovine chromaffin cells followed by the addition of ATP results in a dose-dependent increase in ATP-stimulated InsP formation (EC50 = 2.0 x 10-8 M) which is maximal within one minute. InsP formation resulting from NPY preincubation persists for more than an hour after NPY removal declining with time in a linear fashion. [Leu31Pro34]NPY and NPY are equally effective at producing sensitization whereas NPY13-36 is ineffective suggesting that NPY acts through the Y1 receptor. Confirmation of the receptor subtype identity was made by including the Y1 selective antagonist, HU- 404, during the preincubation, which prevented the sensitizing effect of NPY. NPY sensitization was blocked by pertussis toxin pretreatment demonstrating Gi/Go involvement. ATP-stimulated InsP formation, with and without NPY preincubation, was sensitive to the phospholipase C inhibitor, U73122. In conclusion, short term exposure of bovine chromaffin cells to NPY results in a long-lasting increase in the subsequent stimulation of InsP formation by ATP.


Key words: G proteins, chromaffin cell, heterologous sensitization, inositol phosphate, neuropeptide Y, purinergic


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