Inhibition of calcium currents in cultured rat dorsal root ganglion neurones by (−)‐baclofen

Dolphin, Annette; Scott, Roderick H.

doi:10.1111/j.1476-5381.1986.tb09489.x

Cited by 136 publications

(65 citation statements)

References 30 publications

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“…24). GABA B receptors are known to activate G proteins, thereby enhancing inwardly rectifying potassium channels (25,26) or suppressing calcium channels (27,28). As noted above, the reduction of baclofen-induced antinociception in GIRK2-null mutant mice probably results from blockade of postsynaptic GABA B receptor signaling.…”

Section: Discussionmentioning

confidence: 97%

A pervasive mechanism for analgesia: Activation of GIRK2 channels

Blednov

Stoffel

Alva

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

154

116

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G protein-coupled inwardly rectifying potassium channels (GIRKs) provide a common link between numerous neurotransmitter receptors and the regulation of synaptic transmission. We asked whether GIRKs specify a single behavioral action that is produced by drugs acting on the diverse receptors coupled with GIRKs. By using GIRK2-null mutant mice, we found marked reduction or complete elimination of the antinociceptive (hot plate test) effects of ethanol, oxotremorine, nicotine, baclofen, clonidine, and the cannabinoid receptor agonist WIN 55,212. However, ketamine analgesia remained intact. For most drugs, there was a sex difference in antinociceptive action, and the impact of deletion of the GIRK2 channel was less in female mice. The deletion of the GIRK2 channel blocks the opioid-dependent component of stress-induced analgesia (SIA), whereas nonopioid SIA was not changed. We propose that opioid, ␣ adrenergic, muscarinic cholinergic, ␥-aminobutyric acid-B, and cannabinoid receptors are coupled with postsynaptic GIRK2 channels in vivo. Furthermore, this pathway accounts for essentially all of the antinociceptive effects in males, although females appear to recruit additional signal transduction mechanisms for some analgesic drugs.C hemically and pharmacologically diverse drugs reduce nociceptive responses in humans and in animal models of acute pain. Many of these drugs act through G protein coupled receptors and affect multiple pre-and postsynaptic signaling pathways (1, 2). A key question is whether there is a single G protein signal transduction pathway that is important for antinociceptive actions of many different drugs. One candidate for such a signaling system is the G protein-coupled inwardly rectifying potassium channel (GIRK). This assumption is based in part on the observation that weaver mutant mice have a mutation in GIRK2 and display reduced analgesia after either morphine or -opioid agonist (Ϫ)-U-50488 or ethanol administration (3, 4). However, the weaver mutant is not ideal for assessing the role of GIRK2 because the mutation alters the ion selectivity of GIRK2 and produces neuronal degeneration rather than a simple loss of GIRK2 function (5). Targeted mutation has produced mice lacking the GIRK2 protein; these mice lack postsynaptic responses to several neurotransmitters known to act through G protein coupled receptors, but retain normal presynaptic actions of these receptors (6-8). These mice are viable and similar to wild-type controls in many behavioral tests (9-11) and provide a unique approach to defining the role of GIRK2 in drug actions.GIRKs are activated by M 2 muscarinic, ␣ 2 adrenergic, D 2 dopaminergic, histamine, 5HT 1A , A 1 adenosine, ␥-aminobutyric acid (GABA)-B, , , and ␦ opioid, and somatostatin receptors (12, 13). Because many of these neurotransmitter systems are implicated in antinociception, we tested pharmacologically diverse analgesics in GIRK2 knockout mice by using the hot plate test. Because of known sex differences in sensitivity to druginduced analgesia (14), we compared...

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Section: Discussionmentioning

confidence: 97%

A pervasive mechanism for analgesia: Activation of GIRK2 channels

Blednov

Stoffel

Alva

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

154

116

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“…Ca V 2 channels are subject to inhibitory modulation by G protein -coupled receptors, which typically results in a positive shift in the voltage dependence of activation, as well as a slowing of the rate channel activation as channels enter the "reluctant" state (Dunlap and Fischbach 1981;Dolphin and Scott 1986;Holz et al 1986;Bean 1989b;Dolphin 1998Dolphin , 2003b, an effect that can be relieved by strong depolarizations, which shifts the channel to a "willing" state (Ikeda 1991(Ikeda , 1996. This is a major mechanism of negative feedback whereby neurotransmitters can modulate the activity of presynaptic calcium channels via G protein pathways and, thus, influence neurotransmission.…”

Section: G Protein Modulation Of Presynaptic Calcium Channelsmentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

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“…Such a discrepancy between binding and physiological studies may concern different subtypes of GABAA binding sites (Olsen et al, 1981 (Deisz & Lux, 1985;Dolphin & Scott, 1986;Taleb et al, 1986;Holz et al, 1986) which may account for shorter spikes during GABAB receptor activation. In our experiments, ICa2 S was not inhibited by SR 42641 and peak amplitudes and spike durations were not modified (doses up to 100 times the KB).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of ICa2+T, this third Ca2+ current is generally thought to play a major role in spike generation mechanisms rather than on its shape and/or timing (see discussion in Nowycky et al, 1985;Bossu & Feltz, 1986). It should also be borne in mind that any significant decrease in spike duration by GABAB agonists on the rat ganglia also depends on K+ currents (Desarmenien et al, 1985;Dolphin & Scott, 1986) but biophysical experiments are needed to investigate whether the drug is acting directly or indirectly (affecting intracellular Ca2+) on outward currents. This remains an open question, especially since higher doses of SR42641 clearly increase spike duration.…”

Section: Discussionmentioning

confidence: 99%

“…GABA reversal potentials (-4 ± 6 mV, n = 7) were the same in the absence or in the presence of SR42641, as determined by extrapolation or by direct measurement. (Deisz & Lux, 1985;Dolphin & Scott, 1986;Holtz et al, 1986) and, for the sake ofclarity, we focused our attention mainly on this current. Accordingly, long lasting sustained Ca2"…”

Section: Voltage-dependency Of the Antagonismmentioning

confidence: 99%

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