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NEUROPHARMACOLOGY

Neuropeptide Y Receptor-Mediated Sensitization of ATP-Stimulated Inositol Phosphate Formation

Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska

Activation of bovine chromaffin cell neuropeptide Y (NPY) receptors coupled to G_i (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 G_i-linked and G_s- or G_q-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 1 min. 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 G_i/G_o involvement. ATP-stimulated InsP formation, with and without NPY preincubation, was sensitive to the phospholipase C inhibitor, U73122 [1-(6-{[17-3-methoxyestra-1,3,5(10)-trien-17-yl]-amino}hexyl)-1H-pyrrole-2,5-dione]. 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.

Address correspondence to: Dr. Terry D. Hexum, Department of Pharmacology, University of Nebraska Medical Center, 986260 Nebraska Medical Center, Omaha, NE 68198-6260. E-mail: thexum{at}unmc.edu

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