Baclofen reduces GABAA receptor responses in acutely dissociated neurons of bullfrog dorsal root ganglia

✍ Scribed by Zheng-Xiong Xi; Kei Yamada; Masashi Tsurusaki; Takashi Akasu

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 140 KB
• Volume: 26
• Category: Article
• ISSN: 0887-4476
• DOI: 10.1002/(sici)1098-2396(199706)26:2<165::aid-syn7>3.0.co;2-6

✦ Synopsis

The effect of baclofen on the function of the g-aminobutyric acid A (GABA A ) receptor was examined in acutely dissociated neurons of bullfrog dorsal root ganglia (DRG) by using the whole-cell voltage-clamp method. Baclofen (0.1-100 µM) depressed the inward currents produced by GABA (100 µM) and muscimol (100 µM). Baclofen shifted the concentration-response curve for GABA (1 µM-1 mM) downward. Baclofen decreased the maximum response (V max ) to GABA without changing the apparent dissociation constant (K d ), suggesting a noncompetitive antagonism. The effect of baclofen on the GABA current was blocked by antagonists for the GABA B receptor; the rank order of potency was P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 55845A) : 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzylphosphinic acid (CGP 35348) . saclofen : phaclofen. Baclofen produced an irreversible depression of the GABA current in neurons dialyzed with an internal solution containing guanosine 58-O-(3-thiotriphosphate) (GTPgS, 100 µM). Intracellular guanosine 58-O-(2thiodiphosphate) (GDPbS, 100 µM) blocked the inhibitory effect of baclofen on the GABA current. Forskolin (10 µM) and dibutyryl N 6 , 28-O-dibutyryladenosine 3':58-cyclic monophophate (db-cyclic AMP) (200 µM) depressed the GABA current. N-(2-aminoethyl)-5isoquinolinesulfonamide (H-9, 40 µM) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 50 µM), protein kinase A (PKA) inhibitors, reduced the depressant effect of baclofen on the GABA current. The baclofen-induced depression of the GABA current was blocked by PKI(5-24), a specific PKA inhibitor, but not by PKC(19-36), a specific protein kinase C (PKC) inhibitor. We suggest that GABA B receptors regulate the GABA A receptor function through a G-protein linked to the adenylyl cyclase-PKA pathway in bullfrog DRG neurons.