NEUROPEPTIDE-Y(18-36) MODULATES CHROMAFFIN CELL CATECHOLAMINE SECRETION BY BLOCKING THE NICOTINIC RECEPTOR-ION CHANNEL

Neuropeptide Y (NPY) is a widely distributed peptide with varied activ ities including inhibition of [H-3]NE secretion from chromaffin cells. In the present study, we investigated the mechanism through which NPY and NPY fragments inhibit nicotinic receptor induced influx of Na-22( +) and Ca-45(++) into bovine chromaffin cells. Fragments of NPY, inclu ding. NPY13-36, NPY18-36 and NPY26-36, are more potent inhibitors of C a-45(++) and Na-22(+) influx than NPY. High [K+]- and BAY K 8644-induc ed Ca-45(++) influx and veratridine-induced Na-22(+) influx are not in hibited by either NPY or NPY fragments. Thus, the site of NPY or NPY f ragment action is not voltage-gated Ca++ or Na+ channels. A significan t amount of acetylcholine-induced Ca-45(++) influx still occurs in the presence of the voltage-gated Ca++ channel blockers: nifedipine (L-ty pe), omega-conotoxin-GVIA (N-type) and omega-agatoxin-IVA (P-type). NP Y18-36, in the presence of these channel blockers, inhibited the resid ual nicotinic receptor-induced Ca++ influx. The response to NPY18-36 i s not pertussis toxin sensitive. The rank orders of potency for inhibi tion of Ca-45(++) and Na-22(+) are the same: NPY18-36 greater than or equal to NPY26-36 > NPY13-36 > NPY greater than or equal to NPYfree (a cid). Moreover, the IC50 values for NPY18-36 inhibition of Ca-45(++) i nflux and Na-22(+) influx are similar, 0.9 x 10(-6) M and 2.03 x 10(-6 ) M, respectively. Regression analysis for inhibition of these two phe nomena produced a correlation coefficient of .9697 (P < .0003). Regres sion analysis for inhibition of 1,1-dimethyl-4-phenylpiperizinium (DMP P)-stimulated [H-3]Ne secretion vs. inhibition of DMPP-stimutated Na-2 2(+) influx produced a correlation coefficient of .9894 (P < .0001). W e conclude that NPY modifies nicotinic receptor function by blocking t he nicotinic receptor ligand-gated ion channel.