Neuropeptide Y inhibition of nicotinic receptor-mediated chromaffin cell secretion

Neuropeptide Y (NPY), a widely distributed peptide with varied activities, inhibits nicotinic receptor-induced [³H]norepinephrine ([³H]NE) secretion from bovine chromaffin cells. The secretion produced by membrane depolarization with high KCl concentrations or veratridine is not inhibited. Fragments of NPY, such as NPY18-36, are potent inhibitors of [³H]NE secretion, whereas [Leu³¹,Pro³⁴]-NPY and peptide YY have no effect. The response to NPY18-36 is not sensitive to pertussis toxin pretreatment of chromaffin cells. NPY fragments also inhibit nicotinic receptor-induced ⁴⁵Ca⁺⁺ influx but not that induced by KCl or veratridine. The rank orders of potency for inhibition of [³H]NE secretion and ⁴⁵Ca⁺⁺ influx are the same: NPY18-36 ≥ NPY26-36 > NPY13-36. NPY and NPY(free acid) are weak inhibitors of secretion but not ⁴⁵Ca⁺⁺ influx. Moreover, the IC₅₀s for NPY18-36 inhibition of [³H]NE secretion and ⁴⁵Ca⁺⁺ influx are comparable, 1.4 x 10^-6 M and 0.9 x 10^-6 M, respectively. Regression analysis produced a correlation coefficient of 0.9842 (P < .0001). It was concluded that NPY inhibits [³H]NE secretion by a modification of the nicotinic receptor-mediated increase in Ca⁺⁺ influx. The characterization of the response suggests that the NPY effect is mediated by a previously undefined NPY receptor subtype that was designated Y₄.