Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors

J Neurosci. 2009 Jul 1;29(26):8612-9. doi: 10.1523/JNEUROSCI.1057-09.2009.

Abstract

The Mas-related G protein-coupled receptor D (Mrgprd) is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically relevant somatosensory stimuli that activate Mrgprd-expressing (Mrgprd(+)) neurons are currently unknown. To address these issues, we studied three Mrgprd knock-in mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd(+) afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of green fluorescent protein reporters, was expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat, and mechanical stimuli. Additionally, in vitro patch-clamp studies were performed on cultured dorsal root ganglion neurons from Mrgprd(-/-) and Mrgprd(+/-) mice. These studies revealed a higher rheobase in neurons from Mrgprd(-/-) mice than from Mrgprd(+/-) mice. Furthermore, the application of the Mrgprd ligand beta-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd(+/-) mice but was without effect in neurons from Mrgprd(-/-) mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biophysics
  • Biotin / analogs & derivatives
  • Biotin / metabolism
  • Calcitonin Gene-Related Peptide / metabolism
  • Ganglia, Spinal / cytology*
  • Green Fluorescent Proteins / genetics
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nociceptors / classification*
  • Nociceptors / drug effects
  • Nociceptors / physiology*
  • Patch-Clamp Techniques / methods
  • Peripheral Nerves / physiology
  • Physical Stimulation / methods
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Sensory Thresholds / drug effects
  • Sensory Thresholds / physiology
  • Skin / innervation*
  • Spinal Cord / physiology
  • TRPV Cation Channels / metabolism
  • beta-Alanine / pharmacology

Substances

  • Mrgprd protein, mouse
  • Receptors, G-Protein-Coupled
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • enhanced green fluorescent protein
  • neurobiotin
  • beta-Alanine
  • Green Fluorescent Proteins
  • Biotin
  • Calcitonin Gene-Related Peptide