Received for publication July 6, 2006.
Revised October 17, 2006.
Accepted for publication October 18, 2006.

Neurokinin 1 receptors trigger overlapping stimulation and inhibition of Ca_V2.3 (R-type) calcium channels

Abstract

Neurokinin 1 (NK1) receptors and Ca_V2.3 calcium channels are both expressed in nociceptive neurons, and mice lacking either protein display altered responses to noxious stimuli. Here, we examined modulation of Ca_V2.3 through NK1 receptors expressed in HEK293 cells. We find that NK1 receptors generate complex modulation of Ca_V2.3. Specifically, weak activation of these receptors evokes mainly stimulation of Ca_V2.3, whereas strong receptor activation elicits profound inhibition that overlaps with channel stimulation. Unlike R-type channels encoded by Ca_V2.3, L-type (Ca_V1.3), N-type (Ca_V2.2) and P/Q-type (Ca_V2.1) channels are inhibited, but not stimulated, through NK1 receptors. Pharmacological experiments show that protein kinase C (PKC) mediates stimulation of Ca_V2.3 through NK1 receptors. The signaling mechanisms underlying inhibition were explored by expressing proteins that buffer either Gq/11 (RGS3T and PLC1ct) or G subunits (transducin and MAS-GRK3ct). A fast component of inhibition was attenuated by buffering G, whereas a slow component of inhibition was reduced by buffering Gq/11. When both G and Gq/11 were simultaneously buffered in the same cells, inhibition was virtually eliminated but receptor activation still triggered substantial stimulation of Ca_V2.3. We also report that NK1 receptors accelerate the inactivation kinetics of Ca_V2.3 currents. Altogether, our results indicate that NK1 receptors modulate Ca_V2.3 using three different signaling mechanisms: a fast inhibition mediated by G, a slow inhibition mediated by Gq/11 and a slow stimulation mediated by PKC. This new information concerning R-type calcium channels and NK1 receptors may help in understanding nociception, synaptic plasticity and other physiological processes.

Key words: Neuropeptides, Tachykinin, Calcium (Votage-Gated Channels), Gq/11 family, Phospholipase C's, Protein Kinase C, G protein regulation, RGS proteins, Desensitization/uncoupling, GRKs, barrestins

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