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Zhang, Y.* ; Jiang, D. ; Li, H.* ; Sun, Y.* ; Jiang, X.* ; Gong, S.* ; Qian, Z.* ; Tao, J.*

Melanocortin type 4 receptor-mediated inhibition of A-type K+ current enhances sensory neuronal excitability and mechanical pain sensitivity in rats.

J. Biol. Chem. 294, 5496-5507 (2019)

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alpha-Melanocyte-stimulating hormone (-MSH) has been shown to be involved in nociception, but the underlying molecular mechanisms remain largely unknown. In this study, we report that -MSH suppresses the transient outward A-type K+ current (I-A) in trigeminal ganglion (TG) neurons and thereby modulates neuronal excitability and peripheral pain sensitivity in rats. Exposing small-diameter TG neurons to -MSH concentration-dependently decreased I-A. This -MSH-induced I-A decrease was dependent on the melanocortin type 4 receptor (MC4R) and associated with a hyperpolarizing shift in the voltage dependence of A-type K+ channel inactivation. Chemical inhibition of phosphatidylinositol 3-kinase (PI3K) with wortmannin or of class I PI3Ks with the selective inhibitor CH5132799 prevented the MC4R-mediated I-A response. Blocking G(i/o)-protein signaling with pertussis toxin or by dialysis of TG neurons with the G-blocking synthetic peptide QEHA abolished the -MSH-mediated decrease in I-A. Further, -MSH increased the expression levels of phospho-p38 mitogen-activated protein kinase, and pharmacological or genetic inhibition of p38 abrogated the -MSH-induced I-A response. Additionally, -MSH significantly increased the action potential firing rate of TG neurons and increased the sensitivity of rats to mechanical stimuli applied to the buccal pad area, and both effects were abrogated by I-A blockade. Taken together, our findings suggest that -MSH suppresses I-A by activating MC4R, which is coupled sequentially to the G complex of the G(i/o)-protein and downstream class I PI3K-dependent p38 signaling, thereby increasing TG neuronal excitability and mechanical pain sensitivity in rats.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Electrophysiology ; Patch Clamp ; Potassium Channel ; Signal Transduction ; G-protein-coupled Receptor (gpcr) ; Ion Channel ; Pain ; Cell Signaling ; A-type K Plus Current ; Alpha-melanocyte-stimulating Hormone ; Melanocortin Type 4 Receptor (mc4r) ; Neuronal Excitability ; Trigeminal Ganglion Neurons ; Pain Perception ; Nociception ; Action Potential; Melanocyte-stimulating Hormone; Kv4.2 Potassium Channel; Protein-kinase; Neuropathic Pain; Phosphatidylinositol 3-kinase; Ganglion Neurons; Calcium-channels; P38 Mapk; Activation; Expression

ISSN (print) / ISBN 0021-9258

e-ISSN 1083-351X

Journal Journal of Biological Chemistry, The

Quellenangaben Volume: 294, Issue: 14, Pages: 5496-5507

Publisher American Society for Biochemistry and Molecular Biology

Publishing Place 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)