GABAA receptors in the thalamus: α4 subunit expression and alcohol sensitivity

Fan, Jia; Pignataro, Leonardo; Harrison, Neil L.

doi:10.1016/j.alcohol.2007.03.010

Cited by 44 publications

(37 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding that acute ethanol exposure increased tonic current activity is consistent with previous studies in other brain regions (Jia et al, 2007;Santhakumar et al, 2007;Shen et al, 2011;Herman et al, 2013); however, to our knowledge this is the first report of increased tonic current inhibition after acute ethanol treatment in cortical neurons. If the direct involvement of PKA in mediating this increase is generalized to other brain regions, this finding could have broad implications for a potential role of PKA in ethanol effects on these receptors.…”

Section: Discussionsupporting

confidence: 82%

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Carlson

Bohnsack

Patel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Ethanol produces changes in GABA A receptor trafficking and function that contribute to ethanol dependence symptomatology. Extrasynaptic g-aminobutyric acid A receptors (GABA A -R) mediate inhibitory tonic current and are of particular interest because they are potentiated by physiologically relevant doses of ethanol. Here, we isolate GABA A a4d receptors by western blotting in subsynaptic fractions to investigate protein kinase A (PKA) and protein kinase C (PKC) modulation of ethanol-induced receptor trafficking, while extrasynaptic receptor function is determined by measurement of tonic inhibition and responses evoked by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or PKA/PKC modulators. Ethanol exposure (1 hour) did not alter GABA A a4 receptor abundance, but it increased tonic current amplitude, an effect that was prevented by inhibiting PKA, but not PKC. Direct activation of PKA, but not PKC, increased the abundance and tonic current of extrasynaptic a4d receptors. In contrast, prolonged ethanol exposure (4 hours) reduced a4d receptor abundance as well as tonic current, and this effect was also PKA dependent. Finally, PKC activation by ethanol or phorbol-12,13-dibutyrate (PdBu) had no effect on extrasynaptic a4d subunit abundance or activity. We conclude that ethanol alters extrasynaptic a4d receptor function and expression in cortical neurons in a PKA-dependent manner, but ethanol activation of PKC does not influence these receptors. These results could have clinical relevance for therapeutic strategies to restore normal GABAergic functioning for the treatment of alcohol use disorders.

show abstract

Section: Discussionsupporting

confidence: 82%

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Carlson

Bohnsack

Patel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…Receptors exhibit different spatial and temporal expression in the mammalian CNS (Pirker et al, 2000), and the structural differences in each subunit account for differences in receptor pharmacology, subcellular localization, and intrinsic channel kinetics (Lavoie et al, 1997). Receptors concentrated in the synapse provide brief but strong inhibition, whereas those located more diffusely in perisynaptic or extrasynaptic locations can cause a long-lived inhibitory shunt in response to ambient GABA, which is often amplified by neurosteroids or the presence of alcohol (Jia et al, 2007;Belelli et al, 2009).…”

Section: Gaba a Receptorsmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

176

166

View full text Add to dashboard Cite

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

show abstract

“…Subsequently, ethanol was shown to potentiate Xenopus oocyte-expressed ␣ 4 ␤ 3 ␦ and ␣ 6 ␤ 3 ␦ recombinant receptors at concentrations Ն3 mM and the imidazobenzodiazepine Ro 15-4513 competitively blocked this effect (Wallner et al, 2003Hanchar et al, 2006;Olsen et al, 2007). Tonic currents mediated by ␣ 4 ␤ x ␦ GABA A -Rs in dentate gyrus granule cells and ventrobasal thalamic neurons were shown to be significantly potentiated by ethanol (Ն30 mM) in a protein kinase C␦-dependent manner (Wei et al, 2004;Liang et al, 2006;Fleming et al, 2007;Jia et al, 2007;Messing et al, 2007;Mody et al, 2007). Glykys et al (2007) reported that ethanol (Ն20 mM) enhances ␣ 1 ␤ x ␦ GABA A -R-dependent currents in hippocampal molecular layer interneurons.…”

mentioning

confidence: 99%

Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α₆ GABA_A Receptor Subunit

Botta

Mameli²,

Floyd³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Cerebellar granule neurons (CGNs) extrasynaptically express GABA A receptors containing ␣ 6 ␤ x ␦ subunits, which mediate tonic inhibitory currents. Although it has been shown that the function of these receptors is potently and directly enhanced by ethanol, this finding has not been reproducible across different laboratories. In outbred Sprague-Dawley rats, a naturally occurring arginine (R) to glutamine (Q) mutation in position 100 of the ␣ 6 subunit was reported to increase the ethanol sensitivity of these receptors. However, we did not detect an action of this mutation in selectively bred rats (alcohol-tolerant and alcoholnontolerant). Consequently, we reexamined the effect of the mutation on ethanol sensitivity in Sprague-Dawley rats. Using patch-clamp electrophysiological techniques in cerebellar vermis parasagittal slices, we found that 25 mM ethanol increases the tonic current amplitude, tonic current noise, and spontaneous inhibitory postsynaptic current (sIPSC) frequency to a similar extent in ␣ 6 -100R/100R and ␣ 6 -100Q/100Q CGNs. Exposure to 80 mM ethanol increased the tonic current amplitude to a significantly greater extent in ␣ 6 -100R/100R than in ␣ 6 -100Q/ 100Q CGNs; however, the effects of 80 mM ethanol on the tonic current noise and sIPSC frequency were not significantly different between these groups. In the presence of tetrodotoxin, a non-N-methyl-D-aspartate receptor antagonist, exogenous GABA, and a GABA transporter inhibitor, neither 8 nor 40 mM ethanol consistently affected tonic current amplitude or noise in ␣ 6 -100R/100R or ␣ 6 -100Q/100Q CGNs. Thus, the ␣ 6 -R100Q GABA A receptor subunit polymorphism does not increase the acute ethanol sensitivity of extrasynaptic receptors, lending further support to the hypothesis that ethanol modulates these currents indirectly via a presynaptic mechanism.Studies indicate that ethanol enhances GABAergic transmission in several brain regions via presynaptic and postsynaptic mechanisms (reviewed in Siggins et al., 2005;

show abstract

GABAA receptors in the thalamus: α4 subunit expression and alcohol sensitivity

Cited by 44 publications

References 69 publications

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α₆ GABA_A Receptor Subunit

Contact Info

Product

Resources

About

GABAA receptors in the thalamus: α4 subunit expression and alcohol sensitivity

Cited by 44 publications

References 69 publications

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α6 GABAA Receptor Subunit

Contact Info

Product

Resources

About

Ethanol Sensitivity of GABAergic Currents in Cerebellar Granule Neurons Is Not Increased by a Single Amino Acid Change (R100Q) in the α₆ GABA_A Receptor Subunit