Cutaneous Sensory Neurons Expressing the Mrgprd Receptor Sense Extracellular ATP and Are Putative Nociceptors

1 Vollum Institute L474, Oregon Health and Science University, Portland, Oregon; 2 Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina; and 3 Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California Submitted 26 December 2007; accepted in final form 23 January 2008 Sensory neurons expressing the Mrgprd receptor are known to innervate the outermost living layer of the epidermis, the stratum granulosum. The sensory modality that these neurons signal and the stimulus that they respond to are not established, although immunocytochemical data suggest they could be nonpeptidergic nociceptors. Using patch clamp of dissociated mouse dorsal root ganglion (DRG) neurons, the present study demonstrates that Mrgprd+ neurons have several properties typical of nociceptors: long-duration action potentials, TTX-resistant Na + current, and Ca 2+ currents that are inhibited by mu opioids. Remarkably, Mrgprd+ neurons respond almost exclusively to extracellular ATP with currents similar to homomeric P2X3 receptors. They show little or no sensitivity to other putative nociceptive agonists, including capsaicin, cinnamaldehyde, menthol, pH 6.0, or glutamate. These properties, together with selective innervation of the stratum granulosum, indicate that Mrgprd+ neurons are nociceptors in the outer epidermis and may respond indirectly to external stimuli by detecting ATP release in the skin. Present address and address for reprint requests and other correspondence: G. Dussor, Dept. of Pharmacology, The University of Arizona College of Medicine, PO Box 245050, Tucson, AZ 85724-5050 (E-mail: dussorg{at}email.arizona.edu )