Substance P regulates Ih via a NK-1 receptor in vagal sensory neurons of the ferret.

Substance P (SP) hyperpolarizes approximately 80% of ferret vagal sensory neurons (nodose ganglion neurons) via NK-1 receptor-mediated activation of a potassium current (IK). A depolarizing current activated by membrane hyperpolarization could minimize the SP-induced hyperpolarization. Such a current exists in 65% of the nodose neurons (n = 264). In this study, we examine this current and how it can interact with SP-induced membrane hyperpolarizations. This slowly developing, noninactivating inward current, designated Ih, was activated maximally at about -120 mV and had a reversal potential value of -23 +/- 4.4 mV (n = 4). The time course of activation followed voltage-dependent, monoexponential kinetics. Steady-state activation curves derived from tail current analysis were well fit by a Boltzmann equation yielding a half-activation potential (V1/2) of-77 +/- 1.5 mV and a ks value of 18 +/- 0.5 (n = 8). In the presence of 1 mM cesium, the current was completely abolished. These parameters are consistent with those derived for Ih in other neurons. Substance P (200 nM) reduced the magnitude of Ih elicited by membrane hyperpolarizations to about -110 mV but did not affect the magnitude of Ih elicited by hyperpolarizations to more negative potentials. Tail current analysis revealed that this effect was the result of a SP-induced shift of the Ih activation curve to more negative membrane potentials. The V1/2 value for Ih was shifted by -20 +/- 1.4 mV in the presence of SP with no change in ks (18 +/- 0.7; n = 5). The SP effect on Ih, like its effect on IK, was blocked reversibly by 10 nM CP99,994, a NK-1 antagonist, and was mimicked by the NK-1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASMSP; 200 nM). Ih was not affected by NK-2 or NK-3 selective agonists (n = 4 for each) nor was the effect of SP on Ih reduced by an NK-2 antagonist (n = 4). These results show that SP activates a NK-1 receptor coupled to the Ih channel. Thus NK-1 receptor activation in ferret vagal afferents not only leads to membrane hyperpolarization but it also can enhance synergistically this inhibitory effect by decreasing Ih.