GABAB receptors inhibit low-voltage activated and high-voltage activated Ca2+ channels in sensory neurons via distinct mechanisms

Abstract

Abbreviations: DRG, dorsal root ganglion; DTT, dithiothreitol; GABA, gamma-aminobutyric acid; GFP, green fluorescent protein; HEK293, human embryonic kidney 293 cells; HVA, high voltage activated Ca 2+ channels; LVA, low voltage activated Ca 2+ channels; NK1, neurokinin receptor isoform 1; ROS, reactive oxygen species; PTX, pertussis toxin; VGCC, voltage-gated Ca 2+ channels Abstract Growing evidence suggests that mammalian peripheral somatosensory neurons express functional receptors for gamma-aminobutyric acid, GABAA and GABAB. Moreover, local release of GABA by pain-sensing (nociceptive) nerve fibres has also been suggested. Yet, the functional significance of GABA receptor triggering in nociceptive neurons is not fully understood. Here we used patchclamp recordings from small-diameter cultured DRG neurons to investigate effects of GABAB receptor agonist baclofen on voltage-gated Ca 2+ currents. We found that baclofen inhibited both low-voltage activated (LVA, T-type) and high-voltage activated (HVA) Ca 2+ currents in a proportion of DRG neurons by 22% and 32% respectively; both effects were sensitive to Gi/o inhibitor pertussis toxin. Inhibitory effect of baclofen on both current types was about twice less efficacious as compared to that of the -opioid receptor agonist DAMGO. Surprisingly, only HVA but not LVA current modulation by baclofen was partially prevented by G protein inhibitor GDP--S. In contrast, only LVA but not HVA current modulation was reversed by the application of a reducing agent dithiothreitol (DTT). Inhibition of T-type Ca 2+ current by baclofen and the recovery of such inhibition by DTT were successfully reconstituted in the expression system. Our data suggest that inhibition of LVA current in DRG neurons by baclofen is partially mediated by an unconventional signaling pathway that involves a redox mechanism. These findings reinforce the idea of targeting peripheral GABA receptors for pain relief.

GABA‐producing Bifidobacterium dentium modulates visceral sensitivity in the intestine

“…As reported by other groups, this receptor distribution may coordinate GABAergic regulation of intestinal motility, gastric emptying, gastric acid secretion, and transient lower esophageal sphincter relaxation . Interestingly, a recent in vitro study showed that the GABA agonist baclofen decreased DRG neuron activity by acting on GABA B receptors and inhibiting both low‐voltage activated and high‐voltage activated Ca 2+ currents . γ ‐aminobutyric acid has also recently been shown to act via the GABA B1 receptor on peripheral nociceptive terminals to modulate nociceptor sensitization and counteract inflammatory pain via interaction with the pain receptor, TRPV1 .…”

GABAB receptors-mediated tonic inhibition of glutamate release from Aβ fibers in rat laminae III/IV of the spinal cord dorsal horn

“…9 In laminae I-II, electrophysiological studies performed in rat demonstrated that the exogenous or endogenous activation of presynaptic GABA B Rs inhibits the release of peptides and glutamate from the primary afferent terminals of Aδ and C types 5,10–14 and decreases the release of GABA and glycine from the spinal inhibitory interneurons. 14–16 The depression of neurotransmitter release mediated by GABA B Rs derives from the concurrent inhibition of presynaptic calcium channels 17–19 and release machinery downstream Ca 2+ entry into the nerve terminals. 20 …”

Genetic alteration of the metal/redox modulation of Cav3.2 T‐type calcium channel reveals its role in neuronal excitability

“…This redox modulation of Cav3.2 channels could also be involved in the GABA B receptor inhibition of T‐type channels in DRG neurons (Huang et al . ). Of interest, it was recently reported that chelating zinc with TPEN could facilitate modulation of GABAergic inhibitory post‐synaptic currents in hippocampal granule cells, an effect that was occluded when blocking T‐type channels (Grauert et al .…”

“…In addition, other studies have suggested that the endogenous gasotransmitters, such as hydrogen sulfide (H 2 S) and carbon monoxide (CO), could also play a role in Cav3.2 channel regulation through redox-related mechanisms involving H191 (Boycott et al 2013;Elies et al 2014;Sekiguchi et al 2014). This redox modulation of Cav3.2 channels could also be involved in the GABA B receptor inhibition of T-type channels in DRG neurons (Huang et al 2015). Of interest, it was recently reported that chelating zinc with TPEN could facilitate modulation of GABAergic inhibitory post-synaptic currents in hippocampal granule cells, an effect that was occluded when blocking T-type channels (Grauert et al 2014).…”