GABAC-receptor stimulation activates cAMP-dependent protein kinase via A-kinase anchoring protein 220.
In our previous study, anti-apoptotic effects of GABA(C)-receptor stimulation was suppressed by inhibitors of cAMP-dependent protein kinase (PKA), implying GABA(C) receptor-mediated PKA activation. The present study showed that GABA(C)-receptor stimulation with its agonist, cis-4-aminocrotonic acid (CACA), protected cultured hippocampal neurons from amyloid beta 25 - 35 (Abeta25 - 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 GABA(C)-receptor antagonist, (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA). To test the possibility of GABA(C) receptor-mediated PKA activation, association of GABA(C) 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 GABA(C)-receptor rho subunits precipitated each rho subunit, AKAP220, and PKA regulatory and catalytic subunits from rat brain lysates, suggesting that rho is associated with the AKAP220/PKA complex. Furthermore, antisense oligonucleotide of AKAP220 suppressed such GABA(C) stimulation-induced PKA activation, suggesting that GABA(C)-receptor stimulation activates PKA via AKAP220.
Yang
Li
L
Department of Pharmacology, Kansai Medical University, Moriguchi, Osaka, Japan.
Nakayama
Yasuhisa
Y
Hattori
Naoki
N
Liu
Bing
B
Inagaki
Chiyoko
C
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D003437:Crotonates / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D010721:Phosphinic Acids / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021122:Protein Subunits; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D011963:Receptors, GABA-A; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
C101879:(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; D054758:A Kinase Anchor Proteins; D016229:Amyloid beta-Peptides; D002227:Carbazoles; D003437:Crotonates; D018755:GABA Agonists; D018756:GABA Antagonists; C528239:Gabrr1 protein, rat; D007546:Isoquinolines; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D010721:Phosphinic Acids; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D011725:Pyridines; D011758:Pyrroles; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D013449:Sulfonamides; C074636:amyloid beta-protein (25-35); C055331:4-aminocrotonic acid; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide