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

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α-Melanocyte–stimulating hormone (α-MSH) has been shown to be involved in nociception, but the underlying molecular mechanisms remain largely unknown. In this study, we report that α-MSH suppresses the transient outward A-type K+ current (IA) in trigeminal ganglion (TG) neurons and thereby modulates neuronal excitability and peripheral pain sensitivity in rats. Exposing small-diameter TG neurons to α-MSH concentration-dependently decreased IA. This α-MSH–induced IA 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 IA response. Blocking Gi/o-protein signaling with pertussis toxin or by dialysis of TG neurons with the Gβγ-blocking synthetic peptide QEHA abolished the α-MSH–mediated decrease in IA. Further, α-MSH increased the expression levels of phospho-p38 mitogen-activated protein kinase, and pharmacological or genetic inhibition of p38α abrogated the α-MSH–induced IA response. Additionally, α-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 IA blockade. Taken together, our findings suggest that α-MSH suppresses IA by activating MC4R, which is coupled sequentially to the Gβγ complex of the Gi/o-protein and downstream class I PI3K-dependent p38α signaling, thereby increasing TG neuronal excitability and mechanical pain sensitivity in rats.

electrophysiology
patch clamp
potassium channel
signal transduction
G-protein-coupled receptor (GPCR)
ion channel
pain
cell signaling
A-type K+ current
alpha-melanocyte-stimulating hormone
melanocortin type 4 receptor (MC4R)
neuronal excitability
trigeminal ganglion neurons
pain perception
nociception
action potential

Cited by (0)

This work was supported by National Natural Science Foundation of China Grants 81873731, 81771187, 81622014, 81671080, 81571063, and 81371229; the Innovation Project of Jiangsu Province Qing-Lan Project (to J. T.); Six Talent Peaks Project of Jiangsu Province Grant JY-065; Jiangsu Key Laboratory of Neuropsychiatric Diseases Grant BM2013003; and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors declare that they have no conflicts of interest with the contents of this article.

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Both authors contributed equally to this work.

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The abbreviations used are:

    α-MSH

    α-melanocyte–stimulating hormone

    MC4R

    melanocortin type 4 receptor

    TG

    trigeminal ganglion

    Kv

    voltage-gated K+ channel(s)

    IA

    transient outward K+ channel current(s)

    IDR

    sustained delayed-rectifier K+ channel current(s)

    PI3K

    phosphatidylinositol 3-kinase

    PKA

    protein kinase A

    MAPK

    mitogen-activated protein kinase

    CGRP

    calcitonin gene–related peptide

    4-AP

    4-aminopyridine

    POMC

    proopiomelanocortin

    CCI

    chronic constriction injury

    CTX

    cholera toxin

    PTX

    pertussis toxin

    NC

    negative control

    AP

    action potential

    ERK

    extracellular signal–regulated kinase

    JNK

    c-Jun N-terminal kinase

    SAPK

    stress-activated protein kinase

    GAPDH

    glyceraldehyde-3-phosphate dehydrogenase

    ANOVA

    analysis of variance.