MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability

J Neurosci. 2007 Apr 18;27(16):4492-6. doi: 10.1523/JNEUROSCI.4932-06.2007.


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, beta-alanine, resulted in robust inhibition of KCNQ2/3 activity. Pharmacological blockade of G(i/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, beta-alanine-induced activation of endogenous MrgD inhibited M-currents, but primarily via a pertussis toxin-sensitive pathway. Finally, we assessed the consequence of beta-alanine-induced activation of MrgD in phasic neurons. Phasic neurons that fired a single action potential (AP) before beta-alanine application fired multiple APs during beta-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.

MeSH terms

  • Action Potentials / physiology
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Ganglia, Spinal / metabolism*
  • KCNQ2 Potassium Channel / metabolism*
  • KCNQ3 Potassium Channel / metabolism*
  • Male
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / metabolism*


  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Kcnq2 protein, rat
  • Kcnq3 protein, rat
  • Mas-related receptor MrgD, rat
  • Receptors, G-Protein-Coupled