AUTORECEPTOR-INDUCED INHIBITION OF NEUROPEPTIDE-Y RELEASE FROM PC-12 CELLS IS MEDIATED BY Y-2 RECEPTORS

Pheochromocytoma (PC)-12 cells express Y-1, Y-2, and Y-3 neuropeptide Y (NPY) receptors when differentiated with nerve growth factor (NGF). The present work evaluated NGF-differentiated PC-12 cells as a model s ystem to study modulation of NPY release by NPY autoreceptors. We demo nstrated that both K+ and nicotine stimulated concomitant release of N PY and dopamine from differentiated PC-12 cells. We also showed in thi s study that NPY release from PC-12 cells was attenuated in a concentr ation-dependent manner by peptide YY (PYY)-(13-36), a selective agonis t for the Y-2 type of NPY receptors. This result demonstrated that NPY release could be modulated by NPY autoreceptors of the Y-2 subtype. T he inhibitory action of PYY-(13-36) may be mediated at least in part b y inhibition of N-type Ca2+ channels, because PYY-(13-36) could not pr oduce further inhibitory effects in the presence of a maximum effectiv e concentration of omega-conotoxin, an N-type Ca2+-channel blocker. Th e inhibition by PYY-(13-36) could be blocked by pretreatment of cells with pertussis toxin, suggesting that an inhibitory GTP-binding protei n was involved. Furthermore, the function of NPY autoreceptors could b e modulated by other receptors such as beta-adrenergic and ATP recepto rs. The evoked release of NPY was also attenuated by ATP and adenosine , which have been shown to be colocalized and coreleased with NPY from sympathetic nerve terminals. These results suggest that PC-12 cells d ifferentiated with NGF may be an ideal model to study regulatory mecha nisms of NPY release and that autoreceptor-mediated regulation of NPY release appears to act through the Y-2 subtype of the NPY receptor.