Differential regulation of synaptic and extrasynaptic alpha 4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons

The GABA sub(A) alpha 4 subunit exists in two distinct populations of GABA sub(A) receptors. Synaptic GABA sub(A) alpha 4 receptors are localized at the synapse and mediate phasic inhibitory neurotransmission, while extrasynaptic GABA sub(A) 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 alpha 4 expression while protein kinase C (PKC) activation increases alpha 4 subunit expression, and these effects are associated with increased beta 3 S408/409 or gamma 2 S327 phosphorylation respectively. In contrast, PKA activation increases extrasynaptic alpha 4 and delta subunit expression, while PKC activation has no effect. Our findings suggest synaptic and extrasynaptic GABA sub(A) alpha 4 subunit expression can be modulated by PKA to inform the development of more specific therapeutics for neurological diseases that involve deficits in GABAergic transmission.