Activation and modulation of neuronal K+ channels by GABA

doi:10.1016/0166-2236(92)90025-4

Trends in Neurosciences

Volume 15, Issue 2, February 1992, Pages 46-51

https://doi.org/10.1016/0166-2236(92)90025-4 Get rights and content

Abstract

Although the concept of GABA_B receptors was introduced only ten years ago, several actions of GABA_B agonists are already well established. They cause depression of transmitter release, a decrease in voltage-dependent Ca²⁺ conductance and an increase in K₊ conductance. It has recently been reported that GABA also changes the voltage dependence of the transient (‘A’ type) K⁺ channel. Depression of transmitter release by GABA_B agonists may be caused by a decrease in Ca²⁺ conductance, an increase in K⁺ conductance or a modulation of A channels in presynaptic nerve terminals. Slow IPSPs in some neurons are generated by an increase in K⁺ conductance that can be blocked by GABA_B antagonists and pertussis toxin. K⁺ channels of variable amplitude that are blocked by pertussis toxin are activated by GABA_B agonists in cultured hippocampal neurons. Since arachidonic acid activates similar channels in excised patches of membrane, it may form part of a normal second messenger system linking GABA_B receptors to K⁺ channels.

References (48)

N.G. Bowery
Eur. J. Pharmacol.
(1981)
N.G. Bowery
Trends Pharmacol. Sci.
(1989)
F-K. Pierau et al.
Brain Res.
(1973)
K. Dunlap et al.
Trends Neurosci.
(1987)
P. Dutar et al.
Neuron
(1988)
W.F. Colmers et al.
Neurosci. Lett.
(1988)
E. Huston et al.
Neuroscience
(1990)
U. Heinemann et al.
Neurosci. Lett.
(1984)
A.L. Padjen et al.
Brain Res.
(1990)
N.A. Lambert et al.
Brain Res.
(1991)

D.A. Saint et al.

Neurosci. Lett.

(1990)

B. Rudy

Neuroscience

(1988)

I.S. Login et al.

Brain Res.

(1990)

R.B. Innis et al.

Brain Res.

(1988)

R.H. Thalmann

Neurosci. Lett.

(1987)

J.A. Axelrod et al.

Trends Neurosci.

(1988)

D. Piomelli et al.

Trends Pharmacol. Sci.

(1990)

J. Bormann

Trends Neurosci.

(1988)

S.J. Enna et al.

Trends Pharmacol. Sci.

(1987)

T.V. Dunwiddie et al.

Brain Res.

(1990)

L. Sivilotti et al.

Prog. Neurobiol.

(1990)

D.R. Hill et al.

Nature

(1981)

K. Dunlap et al.

J. Physiol.

(1981)

A.C. Dolphin

Annu. Rev. Physiol.

(1990)

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Citation Excerpt :
These effects tend, though not exclusively, to be site directed such that the decrease in Ca2+ is more associated with presynaptic receptors (Dunlap, 1981) while K+ effects are predominantly postsynaptic (Luscher et al., 1997; see Deisz, 1997; Premkumar & Gage, 1994). As a consequence of these effects receptor activation can produce neuronal hyperpolarization (K+ mediated) (Gage, 1992) or a decrease in evoked neurotransmitter release (Ca2+ effect). Both of these events are mediated by G-proteins that are members of the pertussis toxin-sensitive family Giα/Goα (Odagaki & Koyama, 2001; Odagaki et al., 2000).
This chapter forms an introduction to the subsequent chapters in this volume which highlight the significance and potential therapeutic application of GABA_B receptors. It is now 30 years since the GABA_B site was first described in mammalian tissue. Since then much has emerged about its physiological role in the mammalian nervous system and its relationship to other neurotransmitter receptors. It appears to function at pre- and postsynaptic locations as both an auto- and a hetero-receptor where its activation modulates the membrane conductance of Ca²⁺ and K⁺. The receptor is G-protein coupled and was the first to be shown to exist, possibly in multiple forms, as a heterodimer. The primary agonist for the receptor is baclofen and this continues to be used therapeutically as a centrally active muscle relaxant. Other potential applications for agonists are suggested and positive allosteric modulators may provide an alternative and more effective approach. One application of an agonist, for which there are strong positive clinical data, is in gastroesophageal reflux disease where the receptor target is outside the brain. Antagonists of the GABA_B receptor may also have therapeutic applications such as in cognitive deficits, affective disorders, and absence seizures but robust clinical evidence remains to be demonstrated. Each of these applications is also discussed in the chapters that follow.

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Trends in Neurosciences

ViewpointActivation and modulation of neuronal K+ channels by GABA

Abstract

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Brain Res.

Trends Neurosci.

Neuron

Neurosci. Lett.

Neuroscience

Neurosci. Lett.

Brain Res.

Brain Res.

Neurosci. Lett.

Neuroscience

Brain Res.

Brain Res.

Neurosci. Lett.

Trends Neurosci.

Trends Pharmacol. Sci.

Trends Neurosci.

Trends Pharmacol. Sci.

Brain Res.

Prog. Neurobiol.

Nature

J. Physiol.

Annu. Rev. Physiol.

Viewpoint
Activation and modulation of neuronal K⁺ channels by GABA