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The Journal of Neuroscience, April 18, 2007, 27(16):4492-4496; doi:10.1523/JNEUROSCI.4932-06.2007
Brief Communication
MrgD Activation Inhibits KCNQ/M-Currents and Contributes to Enhanced Neuronal Excitability
Robert A. Crozier,1,2 Seena K. Ajit,1 Edward J. Kaftan,1 andMark H. Pausch1 1Wyeth Research, Discovery Neuroscience and 2Wyeth Postdoctoral Program, CN 8000, Princeton, New Jersey 08543-8000
Correspondence should be addressed to Dr. Robert Crozier, Wyeth Research, Discovery Neuroscience, CN 8000, Princeton, NJ 08543-8000. Email: crozier{at}wyeth.com
The recently identified Mas-related gene (Mrg) family of G-protein-coupled receptors is expressed almost exclusively in dorsal root ganglion (DRG) neurons. The expression of one family member, MrgD, is even further confined to IB4+, nonpeptidergic, small-diameter nociceptors. Although the functional consequences of MrgD activation are not known, this expression profile provides intriguing potential for a role in pain sensation or modulation. In a recombinant cell line, we first assessed the functional significance of MrgD activation by coexpressing MrgD with the KCNQ2/3 potassium channel, a channel implicated in pain. Whole-cell voltage-clamp recordings revealed that bath application of the ligand for MrgD, ß-alanine, resulted in robust inhibition of KCNQ2/3 activity. Pharmacological blockade of Gi/o and phospholipase C signaling revealed a partial and complete block of the response, respectively. We extended these observations to dissociated DRG neuron cultures by examining MrgD modulation of M-currents (carried primarily by KCNQ2/3). Here too, ß-alanine-induced activation of endogenous MrgD inhibited M-currents, but primarily via a pertussis toxin-sensitive pathway. Finally, we assessed the consequence of ß-alanine-induced activation of MrgD in phasic neurons. Phasic neurons that fired a single action potential (AP) before ß-alanine application fired multiple APs during ß-alanine exposure. In sum, we provide evidence for a novel interaction between MrgD and KCNQ/M-type potassium channels that contributes to an increase in excitability of DRG neurons and thus may enhance the signaling of primary afferent nociceptive neurons.
Key words: nociceptor; GPCR; ß-alanine; M-current; DRG; excitability
Received Nov. 13, 2006; revised March 22, 2007; accepted March 22, 2007.
Correspondence should be addressed to Dr. Robert Crozier, Wyeth Research, Discovery Neuroscience, CN 8000, Princeton, NJ 08543-8000. Email: crozier{at}wyeth.com
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