Modulation of inwardly rectifying channels by substance P in cholinergic neurones from rat brain in culture.

1. Whole-cell recording was used to investigate the effects of substance P on cultured neurones from the rat nucleus basalis. 2. Brief applications of substance P produced a reduction, about 1 min in duration, of resting membrane conductance. The concentration producing a half-maximal effect was approximately 40 nM, with the continuous presence of substance P resulting in desensitization of the response. 3. The control current-voltage relation exhibited inward rectification over the voltage range -70 to -150 mV, and hyperpolarization produced a time-dependent decrease of current (inactivation). 4. The substance P-sensitive current, obtained by subtracting the current during the presence of the tachykinin from the control current, showed no time-dependent inactivation, though its current-voltage relation also revealed inward rectification, with the reversal potential being approximately equal to the potassium equilibrium potential, Vk. 5. The relation between the substance P-sensitive chord conductance and voltage could be fitted by a Boltzmann equation, with changes in [K+]o shifting this relation along the voltage axis roughly in parallel with the shift in Vk. The maximum conductance was proportional to [( K+]o). 6. Cs+ (0.1 mM) blocked the substance P-sensitive current in a voltage-dependent manner, with an equivalent valency for Cs+ of 1.9. Barium blockage of the substance P-sensitive current was less voltage dependent. 7. Replacement of external Na+ by tetramethylammonium (TMA+) ions reduced the substance P-sensitive current by only 18%. 8. These results indicate that substance P inhibits potassium channels with inward rectifier properties very similar to those of skeletal muscle. 9. Application of sodium nitroprusside did not alter the effect of substance P, suggesting that cyclic GMP plays no role in the channel modulation.