GABA<sub>B</sub>Receptor-Activated Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons

Sodickson, Deborah L.; Bean, Bruce P.

doi:10.1523/jneurosci.16-20-06374.1996

Cited by 267 publications

(266 citation statements)

References 82 publications

(112 reference statements)

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“…Because we used physiological external K þ , the I-V relationship of the GIRK current did not display considerable inward rectification in the hyperpolarizing direction. Consistent with previous publications, 33 baclofen activated the GIRK current in wt pyramidal cells with a half maximal effective concentration in the low micromolar range (Figure 7d). In marked contrast, baclofen was significantly more effective in inducing GIRK current responses in pyramidal cells from tg mice, as indicated by the leftward shift of the dose-response curve and the increase in maximum GIRK current (Figure 7d).…”

Section: Diazepam Response Is Attenuated In Dnactrib Hippocampussupporting

confidence: 92%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Diazepam Response Is Attenuated In Dnactrib Hippocampussupporting

confidence: 92%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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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: 90%

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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“…This property can be reproduced under certain nonlinearity assumptions in the G-protein transduction mechanisms evoked by GABA B receptors; assuming that the binding of four G-proteins is required to activate K ϩ channels is enough to provide a nonlinear stimulus dependence similar to GABA B responses (Destexhe and Sejnowski, 1995). The multiplicity of binding sites of G-proteins is indeed in agreement with the tetrameric structure of K ϩ channels (Hille, 1992) and the cooperativity evidenced in the activation of GABA B responses (Sodickson and Bean, 1996).…”

Section: The Nonlinear Activation Properties Of Gaba B Responsesmentioning

confidence: 81%

Spike-and-Wave Oscillations Based on the Properties of GABA_BReceptors

1998

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Neocortical and thalamic neurons are involved in the genesis of generalized spike-and-wave (SW) epileptic seizures. The cellular mechanism of SW involves complex interactions between intrinsic neuronal firing properties and multiple types of synaptic receptors, but because of the complexity of these interactions the exact details of this mechanism are unclear. In this paper these types of interactions were investigated by using biophysical models of thalamic and cortical neurons. It is shown first that, because of the particular activation properties of GABA B receptor-mediated responses, simulated field potentials can display SW waveforms if cortical pyramidal cells and interneurons generate prolonged discharges in synchrony, without any other assumptions. Here the "spike" component coincided with the synchronous firing, whereas the "wave" component was generated mostly by slow GABA B -mediated K ϩ currents. Second, the model suggests that intact thalamic circuits can be forced into a ϳ3 Hz oscillatory mode by corticothalamic feedback. Here again, this property was attributable to the characteristics of GABA B -mediated inhibition. Third, in the thalamocortical system this property can lead to generalized ϳ3 Hz oscillations with SW field potentials. The oscillation consisted of a synchronous prolonged firing in all cell types, interleaved with a ϳ300 msec period of neuronal silence, similar to experimental observations during SW seizures. This model suggests that SW oscillations can arise from thalamocortical loops in which the corticothalamic feedback indirectly evokes GABA B -mediated inhibition in the thalamus. This mechanism is shown to be consistent with a number of different experimental models, and experiments are suggested to test its consistency.

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GABA_BReceptor-Activated Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons

Cited by 267 publications

References 82 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

A pervasive mechanism for analgesia: Activation of GIRK2 channels

Spike-and-Wave Oscillations Based on the Properties of GABA_BReceptors

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GABABReceptor-Activated Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons

Cited by 267 publications

References 82 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

A pervasive mechanism for analgesia: Activation of GIRK2 channels

Spike-and-Wave Oscillations Based on the Properties of GABABReceptors

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Product

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GABA_BReceptor-Activated Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons

Spike-and-Wave Oscillations Based on the Properties of GABA_BReceptors