Substance P Regulates Ih via a NK-1 Receptor in Vagal Sensory Neurons of
the Ferret.
M. Samir Jafri, Daniel Weinreich.
University of Maryland, School of Medicine, Department of Pharmacology and
Experimental Therapeutics, 685 West Baltimore Street, Baltimore, Maryland, USA
21201-1559.
APStracts 4:292N, 1997.
ABSTRACT
Substance P (SP) hyperpolarizes ÿ7E80% 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,
non-inactivating inward current, designated Ih, was maximally activated at
120 mV and had a reversal potential value of -23 ñ 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«) of -77 ñ 1.5 mV and a ks value of 18 ñ 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 ÿ7E -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 V«
value for Ih was shifted by -20 ñ 1.4 mV in the presence of SP with no change
in ks (18 ñ 0.7; n = 5). The SP effect on Ih, like its effect on IK, was
reversibly blocked by 10 nM CP99,994, an NK-1 antagonist, and was mimicked by
the NK-1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASM-SP; 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 can also synergistically enhance this inhibitory
effect by decreasing Ih.
Received 7 July 1997; accepted in final form 13 October 1997.
APS Manuscript Number J596-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 29 October 1997