title: Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice.
abstract: Mas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist-induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, MD 21201, USA Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USA Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA Department of Human Anatomy, Nanjing Medical University, Nanjing 210029, China Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Shao-Qiu
authors.initials: SQ
authors.lastname: He
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Vinod
authors.initials: V
authors.lastname: Tiwari
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Zongxiang
authors.initials: Z
authors.lastname: Tang
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Chu
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Niyada
authors.initials: N
authors.lastname: Hin
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Barbara
authors.initials: B
authors.lastname: Slusher
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Guan
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D013376:Substantia Gelatinosa / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D020864:Calcium Channels, N-Type; C000591604:MrgC protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Calcium channel; Dorsal root ganglion; MrgC; Nerve injury; Pain