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Neurokinin 1 Receptors Trigger Overlapping Stimulation and Inhibition of Ca_V2.3 (R-Type) Calcium Channels

Department of Physiology and Pharmacology, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (U.M.); and Department of Biology, Utah State University, Logan, Utah (A.T., R.A.B., B.A.A.)

Neurokinin (NK) 1 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 human embryonic kidney 293 cells. We find that NK1 receptors generate complex modulation of Ca_V2.3. In particular, 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 G_q/11 (regulator of G protein signaling protein 3T and carboxyl-terminal region of phospholipase C-1) or G subunits (transducin and the carboxyl-terminal region of bovine G-protein-coupled receptor kinase). A fast component of inhibition was attenuated by buffering G, whereas a slow component of inhibition was reduced by buffering G_q/11. When both G and G_q/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 G_q/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.

Address correspondence to: Dr. Brett Adams, Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322. E-mail: brett{at}biology.usu.edu

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