title: Differential regulation of synaptic and extrasynaptic α4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons.
abstract: The GABAA α4 subunit exists in two distinct populations of GABAA receptors. Synaptic GABAA α4 receptors are localized at the synapse and mediate phasic inhibitory neurotransmission, while extrasynaptic GABAA receptors are located outside of the synapse and mediate tonic inhibitory transmission. These receptors have distinct pharmacological and biophysical properties that contribute to interest in how these different subtypes are regulated under physiological and pathological states. We utilized subcellular fractionation procedures to separate these populations of receptors in order to investigate their regulation by protein kinases in cortical cultured neurons. Protein kinase A (PKA) activation decreases synaptic α4 expression while protein kinase C (PKC) activation increases α4 subunit expression, and these effects are associated with increased β3 S408/409 or γ2 S327 phosphorylation respectively. In contrast, PKA activation increases extrasynaptic α4 and δ subunit expression, while PKC activation has no effect. Our findings suggest synaptic and extrasynaptic GABAA α4 subunit expression can be modulated by PKA to inform the development of more specific therapeutics for neurological diseases that involve deficits in GABAergic transmission.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill NC, 27599-7178, USA.
authors.forename: John Peyton
authors.initials: JP
authors.lastname: Bohnsack
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill NC, 27599-7178, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Carlson
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill NC, 27599-7178, USA. Electronic address: morrow@med.unc.edu.
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: C546262:Gabra4 protein, rat; D011963:Receptors, GABA-A; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C
keywords: Expression; GABA(A)(​) receptor; PKA; PKC; Serine phosphorylation; α4 subunit