An update on GABAA receptors

Mehta, Abhishek; Ticku, Maharaj K.

doi:10.1016/s0165-0173(98)00052-6

Cited by 603 publications

(408 citation statements)

References 282 publications

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“…1 GABA A receptors are the ubiquitous ligand-gated chloride ionophores responsible for most rapid inhibition within the central nervous system. [2][3][4] Within the NTS, activation of GABA A receptors inhibits virtually all neurons tested and results in an increase in arterial pressure, heart rate, and sympathetic outflow, effects consistent with inhibitory modulation of arterial baroreceptor reflexes. 1 The function of GABA A receptors has been shown to be modulated by a variety of factors.…”

mentioning

confidence: 66%

“…In response to other perturbations, GABA A receptors have been shown to undergo changes in subunit composition, changes in the number and/or affinity of binding sites, and changes in intracellular calcium and/or phosphorylation state leading to enhanced or reduced conductance. 3,4 All of these possibilities remain avenues for future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Receptor number, subunit composition, and phosphorylation state are but a few of the ways that GABA receptor function can be altered after chronic exposure to alcohol, barbiturates, benzodiazepines, and GABA itself. [2][3][4] Alterations in the responses of NTS neurons to GABA A receptor activation could result in alterations in the integration of afferent inputs, reflex function, and resting cardiovascular parameters. The goal of the current study was to determine if the responses of isolated NTS neurons to activation of GABA A receptors are altered in hypertension.…”

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confidence: 99%

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Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

2004

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Abstract-The inhibitory amino acid GABA is a potent modulator of the spontaneous discharge and the responses to afferent inputs of neurons in the nucleus of the solitary tract (NTS). To determine if responses to activation of GABA A receptors are altered in hypertension, GABA A receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from 33 normotensive (NT, 109Ϯ4 mm Hg, nϭ7) and 24 hypertensive (HT, 167Ϯ5 mm Hg, nϭ24) rats. GABA A receptor-evoked currents reversed at the calculated equilibrium potential for chloride and were blocked by bicuculline (nϭ6). Membrane capacitance was the same in neurons from NT (7.5Ϯ0.6 pF, nϭ62) and HT (6.8Ϯ0.6 pF, nϭ51) rats. The EC 50 for peak GABA-evoked currents cells was significantly greater in neurons from HT (21.0Ϯ2.6 mol/L, nϭ16) compared with NT rats (13.0Ϯ1.8 mol/L, nϭ14, Pϭ0.01). The EC 50 of neurons exhibiting DiA labeling of presumptive aortic nerve terminals was no different than that observed in the nonlabeled cells (19.0Ϯ4.9 mol/L, nϭ4). The time constant for desensitization of GABA A -evoked currents was the same in neurons from HT (4.5Ϯ0.3 seconds, nϭ17) and NT rats (3.8Ϯ0.3 seconds, nϭ17, PϾ0.05). Repetitive pulse application of GABA revealed a more rapid decline in the evoked current in neurons from HT compared with NT rats. The amplitude of the 5th pulse of GABA (5-second duration, 2-second interval) was 21Ϯ2% the amplitude of the 1st pulse in NT rats (nϭ10) and 14Ϯ2% in HT rats (nϭ11, PϽ0.05). These alterations in GABA A -receptor evoked currents could render the neurons less sensitive to GABA A receptor inhibition and influence afferent integration by NTS neurons in HT. [2][3][4] Within the NTS, activation of GABA A receptors inhibits virtually all neurons tested and results in an increase in arterial pressure, heart rate, and sympathetic outflow, effects consistent with inhibitory modulation of arterial baroreceptor reflexes. 1 The function of GABA A receptors has been shown to be modulated by a variety of factors. Receptor number, subunit composition, and phosphorylation state are but a few of the ways that GABA receptor function can be altered after chronic exposure to alcohol, barbiturates, benzodiazepines, and GABA itself. [2][3][4] Alterations in the responses of NTS neurons to GABA A receptor activation could result in alterations in the integration of afferent inputs, reflex function, and resting cardiovascular parameters. The goal of the current study was to determine if the responses of isolated NTS neurons to activation of GABA A receptors are altered in hypertension. Methods GeneralSuccessful experiments were performed on adult (1 to 3 months), male Sprague-Dawley rats (375 to 500 g, Charles River Laboratories or Harlan Sprague-Dawley Inc). Rats were housed 2 per cage in a fully accredited (Association for Assessment and Accreditation of Laboratory Animal Care and the United States Department of Agriculture) laboratory animal room with free access to food and water. All rats were given at least 1 week to acclimat...

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confidence: 66%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

2004

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“…GABA A receptors are ligand-gated chloride channels composed of a pentameric assembly of homologous subunits (46). Since GABA A receptors mediate synaptic inhibition, mutations with reduced activity could produce neuronal hyperexcitability.…”

Section: Ligand-gated Gaba a Receptorsmentioning

confidence: 99%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

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“…Incorporation of an α subunit is required for production of GABAactivated channels in mammalian expression systems and an α subunit is almost certainly present in all native receptors (Fritschy et al, 1997). The α subtypes show relatively high structural homology (60-80%) but confer distinct functional and pharmacological properties (Mehta and Ticku, 1999;Korpi et al, 2002). The mRNA for each of the α subtypes exhibits a unique distribution pattern throughout the rat brain, and is differently regulated throughout development (Laurie et al, 1992a(Laurie et al, , 1992bWisden et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

Picton

Fisher

2007

Brain Research

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The GABA A receptors (GABARs) are chloride-permeable ligand-gated ion channels responsible for fast inhibitory neurotransmission. These receptors are structurally heterogeneous, and in mammals can be formed from a combination of sixteen different subunit subtypes. Much of this variety comes from the six different α subunit subtypes. All neuronal GABARs contain an α subunit, and the identity of the α subtype affects the pharmacological properties of the receptors. The expression of each of the different α subtypes is regulated developmentally and regionally and changes with both normal physiological processes such development and synaptic plasticity, and pathological conditions such as epilepsy. In order to understand the functional significance of this structural heterogeneity, we examined the effect of the α subtype on the receptor's response to GABA. Each of the six α subtypes was transiently co-expressed with the β3 and γ2L subunits in mammalian cells. The sensitivity to GABA was measured with whole-cell recordings. We also determined the activation, deactivation, desensitization, and recovery kinetics for the six isoforms using rapid-application recordings from excised macropatches. We found unique characteristics associated with each α subunit subtype. These properties would be expected to influence the post-synaptic response to GABA, creating functional diversity among neurons expressing different α subunits.

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An update on GABAA receptors

Cited by 603 publications

References 282 publications

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

Identification of Epilepsy Genes in Human and Mouse

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

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