Analysis of G-protein-activated inward rectifying K+ (GIRK) channel currents upon GABAB receptor activation in rat supraoptic neurons

Harayama, Nobuya; Kayano, Tomohiko; Moriya, Taiki; Naoki, Katsuhiko; Shibuya, Izumi; Tanaka-Yamamoto, Keiko; Uezono, Yasuhito; Ueta, Yoichi; Sata, Takeyoshi

doi:10.1016/j.brainres.2014.10.022

Cited by 3 publications

(3 citation statements)

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“…In the present study, we show that Vc1.1 potentiates human GIRK1/2 channels albeit with a 10-to 50-fold lower potency than for inhibition of human Ca v 2.2 channels (Cai et al, 2018;Huynh et al, 2015). In a comparable manner, it was shown that even though GIRK and Ca v 2.2 channels are regulated by GABA B receptors via an analogous mechanism, the EC 50 for GIRK potentiation by baclofen is $100-fold higher than for inhibition of HVA Ca 2+ channels in rat supraoptic neurons (Harayama et al, 2014). Interestingly, a slight variation in basal current densities have been observed et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

“…In the present study, we show that Vc1.1 potentiates human GIRK1/2 channels albeit with a 10‐ to 50‐fold lower potency than for inhibition of human Ca v 2.2 channels (Cai et al, 2018; Huynh et al, 2015). In a comparable manner, it was shown that even though GIRK and Ca v 2.2 channels are regulated by GABA B receptors via an analogous mechanism, the EC 50 for GIRK potentiation by baclofen is ~100‐fold higher than for inhibition of HVA Ca 2+ channels in rat supraoptic neurons (Harayama et al, 2014). Interestingly, a slight variation in basal current densities have been observed in our experimental conditions presumably due to (1) The extent of activation by agonist is inversely related to I basal /GIRK basal current (Yakubovich et al, 2015), (2) based on collision coupling proposed by Kahanovitch et al (2017), increased GABA B receptor expression reduced basal GIRK current activity, and (3) some protein complex family, such as the GTPase activating protein RGS2 and the guanine dissociation inhibitor proteins like LGN, affect or reduce GIRK basal activities in G protein signalling cascade when channels coupled to metabotropic receptors are coupled to Gi or Go, but not Gs (Wiser et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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

Bony

McArthur

Finol‐Urdaneta

et al. 2021

British J Pharmacology

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Background and Purpose: Activation of GIRK channels via G protein-coupled GABA B receptors has been shown to attenuate nociceptive transmission. The analgesic α-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 α-conotoxins on recombinant and native GIRK-mediated K + currents and on neuronal excitability.Experimental Approach: 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 GABA B 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. Key Results: Analgesic α-conotoxins Vc1.1, RgIA, and PeIA 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 α-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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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

Bony

McArthur

Finol‐Urdaneta

et al. 2021

British J Pharmacology

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“…In the present study, we show that Vc1.1 potentiates GIRK1/2 channels albeit with 10- to 100-fold lower potency than for inhibition of human and rat Ca v 2.2 channels (Callaghan & Adams, 2010; Huynh et al , 2015; Hone et al , 2018). In a comparable manner, it was shown that even though GIRK and Cav2.2 channels are regulated by GABA B R by an analogous mechanism, the EC 50 for GIRK potentiation by baclofen is ~100-fold higher than for inhibition of HVA Ca 2+ channels in rat supraoptic neurons (Harayama et al , 2014).…”

Section: Discussionmentioning

confidence: 99%

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability

Bony

McArthur

Finol‐Urdaneta

et al. 2020

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Activation of G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels leads to membrane hyperpolarization and dampening of neuronal excitability. Here we show that the analgesic α-conotoxin Vc1.1 potentiates inwardly rectifying K+ currents (IKir) mediated through native and recombinant GIRK1/2 channels by activation of the G protein-coupled GABAB receptor (GABABR) via a Pertussis toxin (PTX)-sensitive G protein. Recombinant co-expression of human GIRK1/2 subunits and GABABR in HEK293T cells resulted in a Ba2+-sensitive IKir potentiated by baclofen and Vc1.1 which was inhibited by PTX, intracellular GDP-β-S, or the GABABR-selective antagonist CGP 55845. In adult mouse DRG neurons, GABABR-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell resting membrane potential with concomitant reduction of excitability consistent with Vc1.1 and baclofen analgesic effects in vivo. This study provides new insight into Vc1.1 as an allosteric agonist for GABABR-mediated potentiation of GIRK channels and may aid in the development of novel non-opioid treatments for chronic pain.

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Mechanisms of GABA-mediated inhibition of the angiotensin II-induced cytosolic Ca2+ increase in rat subfornical organ neurons

et al. 2021

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Analysis of G-protein-activated inward rectifying K+ (GIRK) channel currents upon GABAB receptor activation in rat supraoptic neurons

Cited by 3 publications

References 65 publications

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

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

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability

Mechanisms of GABA-mediated inhibition of the angiotensin II-induced cytosolic Ca2+ increase in rat subfornical organ neurons

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Analysis of G-protein-activated inward rectifying K+ (GIRK) channel currents upon GABAB receptor activation in rat supraoptic neurons

Cited by 3 publications

References 65 publications

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

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

Analgesic α-conotoxins modulate GIRK1/2 channels via GABABreceptor activation and reduce neuroexcitability

Mechanisms of GABA-mediated inhibition of the angiotensin II-induced cytosolic Ca2+ increase in rat subfornical organ neurons

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Resources

About

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

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

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability