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 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.
Rau
Kristofer K
KK
Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
McIlwrath
Sabrina L
SL
Wang
Hong
H
Lawson
Jeffrey J
JJ
Jankowski
Michael P
MP
Zylka
Mark J
MJ
Anderson
David J
DJ
Koerber
H Richard
HR
D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009619:Nociceptors / Q000145:classification* / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010525:Peripheral Nerves / Q000502:physiology; D010812:Physical Stimulation / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000294:innervation*; D013116:Spinal Cord / Q000502:physiology; D050916:TRPV Cation Channels / Q000378:metabolism; D015091:beta-Alanine / Q000494:pharmacology
C497098:Mrgprd protein, mouse; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C485184:enhanced green fluorescent protein; C070614:neurobiotin; D015091:beta-Alanine; D049452:Green Fluorescent Proteins; D001710:Biotin; D015740:Calcitonin Gene-Related Peptide