GABAC-Receptor Stimulation Activates cAMP-Dependent Protein Kinase via A-Kinase Anchoring Protein 220

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In our previous study, anti-apoptotic effects of GABAC-receptor stimulation was suppressed by inhibitors of cAMP-dependent protein kinase (PKA), implying GABAC receptor–mediated PKA activation. The present study showed that GABAC-receptor stimulation with its agonist, cis-4-aminocrotonic acid (CACA), protected cultured hippocampal neurons from amyloid β 25 – 35 (Aβ25 – 35) peptide–enhanced glutamate neurotoxicity. This protective effect of CACA was blocked by PKA inhibitors, KT 5720 and H-89, as well as a specific GABAC-receptor antagonist, (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA). To test the possibility of GABAC receptor–mediated PKA activation, association of GABAC receptor with A-kinase anchoring proteins (AKAPs) and effect of an AKAP antisense oligonucleotide on the PKA activation were examined in primary cultured rat hippocampal neurons. Stimulation of the cells with CACA-activated PKA was assessed by the phosphorylated PKA substrate (135 kDa) level. Specific antibodies raised against GABAC-receptor ρ subunits precipitated each ρ subunit, AKAP220, and PKA regulatory and catalytic subunits from rat brain lysates, suggesting that ρ is associated with the AKAP220/PKA complex. Furthermore, antisense oligonucleotide of AKAP220 suppressed such GABAC stimulation–induced PKA activation, suggesting that GABAC-receptor stimulation activates PKA via AKAP220.
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