VASOACTIVE INTESTINAL POLYPEPTIDE MODULATION OF NICOTINIC ACH RECEPTOR CHANNELS IN RAT INTRACARDIAC NEURONS

1. The effects of vasoactive intestinal polypeptide (VIP) on isolated parasympathetic neurones of rat intracardiac ganglia were examined und er voltage clamp using dialysed and perforated patch whole-cell and ex cised outside-out membrane patch recording configurations. 2. VIP reve rsibly potentiated nicotinic ACh-evoked whole-cell currents, with half -maximal potentiation (EC(50)) obtained with 260 pM VIP. How-ever, VIP had no effect on muscarinic ACh-evoked currents, ATP-evoked currents, or depolarization-activated ionic currents in these neurones. 3. VIP- induced potentiation of nicotinic ACh-evoked whole-cell currents was o bserved following cell dialysis, and was inhibited reversibly by bath application of the VIP receptor-binding inhibitor L-8-K (5 mu M) or th e neuronal nicotinic receptor antagonist mecamylamine (3 mu M). 4. The signal transduction pathway mediating VIP-induced potentiation of nic otinic ACh-evoked currents involves a guanine nucleotide-binding prote in (G-protein) but not cyclic BMP. Intracellular application of 100 mu M GDP-beta-X, or pre-incubation of neurones with pertussis toxin, inh ibited VIP-induced potentiation of ACh-evoked whole-cell currents. 5. In outside-out membrane patches, co-application of ACh (4 mu M) and VI P (4 nM) decreased the duration of closings between bur sts and cluste rs of bursts of ACh single-channel activity relative to control (4 mu M, ACh alone). VIP, however, did not alter single ACh receptor channel current amplitude, duration of closings and openings within a burst, or mean burst duration. 6. VIP-induced modification of nicotinic ACh r eceptor channel kinetics results in an increase in the open-channel pr obability which is sufficient to account for the VIP-mediated potentia tion of nicotinic ACh-evoked whole-cell currents. 7. The potentiation of nicotinic ACh-evoked currents by VIP is likely to account for the a ltered neuronal activity observed in the mammalian intracardiac gangli a in vivo and consequent changes in heart rate and cardiac contractili ty.