The Journal of Neurophysiology Vol. 79 No. 2 February 1998, pp. 769-777
Copyright ©1998 The American Physiological Society

Substance P Regulates I_h via a NK-1 Receptor in Vagal Sensory Neurons of the Ferret

M. Samir Jafri and Daniel Weinreich

Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, Maryland, 21201-1559

Jafri, M. Samir and Daniel Weinreich. Substance P regulates I_h via a NK-1 receptor in vagal sensory neurons of the ferret. J. Neurophysiol. 79: 769-777, 1998. Substance P (SP) hyperpolarizes ~80% of ferret vagal sensory neurons (nodose ganglion neurons) via NK-1 receptor-mediated activation of a potassium current (I_K). 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 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, monoexponential kinetics. Steady-state activation curves derived from tail current analysis were well fit by a Boltzmann equation yielding a half-activation potential (V_1/2) of77 ± 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 elicited by membrane hyperpolarizations to about 110 mV but did not affect the magnitude of I_h elicited by hyperpolarizations to more negative potentials. Tail current analysis revealed that this effect was the result of a SP-induced shift of the I_h activation curve to more negative 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 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). 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 hyperpolarization but it also can enhance synergistically this inhibitory effect by decreasing I_h.

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