Pancreatic polypeptide inhibits calcium channels in rat sympathetic neurons via two signaling pathways

1. We studied modulation of N-type Ca²⁺ channels in adult rat superior cervical ganglion (SCG) neurons by pancreatic polypeptide (PP) using whole cell clamp. In large (>20 pF) SCG neurons, PP inhibited I(Ca) (35 ± 2%, mean ± SE) in a concentration-dependent fashion, with one-half maximal inhibition at 19 nM. 2. One-third of the inhibition was blocked by pertussis toxin, about one-half was blocked by N-ethylmaleimide (NEM) treatments, and about one-half was voltage dependent. The NEM-insensitive component of the PP inhibition was voltage independent and not significantly blocked by intracellular Ca²⁺ chelators. 3. The NEM-insensitive component was only weakly attenuated by GDP-β-S, and moderately reversible with guanosine 5'- triphosphate (GTP)-γ-S, in the whole cell pipette, leaving open the possibility that it is not mediated by a G protein. 4. Hence, PP inhibits I(Ca) via two mechanisms: one G-protein-mediated and the other possibly G- protein independent. The former pathway is sensitive to pertussis toxin (PTX) and NEM, voltage dependent, and shared by several other transmitters in these cells. The latter pathway is PTX-and NEM-insensitive, not voltage dependent, and not affected by the presence of intracellular Ca²⁺ chelators.