4.7 Article

Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability

期刊

BRITISH JOURNAL OF PHARMACOLOGY
卷 179, 期 1, 页码 179-198

出版社

WILEY
DOI: 10.1111/bph.15690

关键词

baclofen; GABA(B) receptor; GIRK channel; sensory neurons; alpha-conotoxin

资金

  1. Australian National Health and Medical Research Council (NHMRC) Program Grant [APP1072113]

向作者/读者索取更多资源

This study is the first to report the potentiation of GIRK channels via allosteric alpha-conotoxin Vc1.1-GABA(B) receptor agonism, leading to decreased neuronal excitability. This finding contributes to the understanding of the analgesic effects of Vc1.1 and baclofen in vivo.
Background and Purpose: Activation of GIRK channels via G protein-coupled GABA(B) receptors has been shown to attenuate nociceptive transmission. The analgesic alpha-conotoxin Vc1.1 activates GABA(B) receptors resulting in inhibition of Ca-v 2.2 and Ca-v 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic alpha-conotoxins on recombinant and native GIRK-mediated K-1 currents and on neuronal excitability. Experimental Approach: The effects of analgesic alpha-conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly-rectifying K+ currents in HEK293T cells recombinantly alpha-expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABA(B) receptors. The effects of alpha-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. Key Results: Analgesic alpha-conotoxins Vc1.1, RgIA, and PelA potentiate inwardly-rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABA(B) receptors. GABA(B) receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABA(B) receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABA(B) receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability. Conclusions and Implications: This is the first report of GIRK channel potentiation via allosteric alpha-conotoxin Vc1.1-GABA(B) 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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