Mrgprd Enhances Excitability in Specific Populations of Cutaneous Murine Polymodal Nociceptors
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 β-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.
© 2009 Society for Neuroscience. Received March 4, 2009; revised April 28, 2009; accepted May 18, 2009. This work was supported by National Institutes of Health Grants R01 NS23275 and NS052848 (H.R.K) and P01 NS048499-05 (D.J.A.) and the Sloan Foundation, the Searle Scholars Program, the Klingenstein Foundation, the Whitehall Foundation, the Rita Allen Foundation, and National Institute of Neurological Disorders and Stroke Grant R01 NS060725 (all to M.J.Z.). M.J.Z. is a Rita Allen Foundation Milton E. Cassel Scholar. We sincerely thank Collene Anderson and Weiwen Wang for their excellent technical assistance and Liching Lo for assistance in making the Mrgprd-CRE knock-in mouse.
Published - Rau2009p4692J_Neurosci.pdf