SUBSTANCE-P REGULATES I-H VIA A NK-1 RECEPTOR IN VAGAL SENSORY NEURONS OF THE FERRET

Substance P (SP) hyperpolarizes similar to 80% of ferret vagal sensory neurons (nodose ganglion neurons) via NK-1 receptor-mediated activati on of a potassium current (I-K). A depolarizing current activated by m embrane hyperpolarization could minimize the SP-induced hyperpolarizat ion. 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-in duced membrane hyperpolarizations. This slowly developing, noninactiva ting inward current, designated I-h, 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, monoexponent ial kinetics. Steady-state activation curves derived from tail current analysis were well fit by a Boltzmann equation yielding a half-activa tion potential (V-1/2) of -77 +/- 1.5 mV and a k(s) 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 I-h in other neurons. Substance P (200 nM) reduced the magnitude of I-h el icited by membrane hyperpolarizations to about -110 mV but did not aff ect the magnitude of I-h elicited by hyperpolarizations to more negati ve potentials. Tail current analysis revealed that this effect was the result of a SP-induced shift of the I-h activation curve to more nega tive membrane potentials. The V-1/2 value for I-h was shifted by -20 /- 1.4 mV in the presence of SP with no change in k(s) (18 +/- 0.7; n = 5). The SP effect on I-h, like its effect on I-K, was blocked revers ibly by 10 nM CP99,994, a NK-1 antagonist, and was mimicked by the NK- 1 agonist Ac-[Arg(6), Sar(9), Met(O-2)(11)]SP(6-11) (ASMSP; 200 nM). I -h was not affected by NK-2 or NK-3 selective agonists (n = 4 for each ) nor was the effect of SP on I-h reduced by an NK-2 antagonist (n = 4 ). These results show that SP activates a NK-1 receptor coupled to the I-h channel. Thus NK-1 receptor activation in ferret vagal afferents not only leads to membrane hyper polarization but it also can enhance synergistically this inhibitory effect by decreasing I-h.