G蛋白偶联内向整流钾通道
γ-氨基丁酸受体
巴氯芬
化学
药理学
长时程增强
背根神经节
受体
神经科学
作者
Anuja R. Bony,Jeffrey R. McArthur,Rocio K. Finol-Urdaneta,David J. Adams
摘要
Activation of GIRK channels via G protein-coupled GABAB receptors has been shown to attenuate nociceptive transmission. The analgesic α-conotoxin Vc1.1 activates GABAB receptors resulting in inhibition of Cav 2.2 and Cav 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α-conotoxins on recombinant and native GIRK-mediated K+ currents and on neuronal excitability.The effects of analgesic α-conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly-rectifying K+ currents in HEK293T cells recombinantly co-expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABAB receptors. The effects of α-conotoxin Vc1.1 and baclofen were studied on GIRK-mediated K+ currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons.Analgesic α-conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly-rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABAB receptors. GABAB receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABAB receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABAB receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability.This is the first report of GIRK channel potentiation via allosteric α-conotoxin Vc1.1-GABAB receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.
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