Inhibition by adenosine A(2A) receptors of NMDA but not AMPA currents in rat neostriatal neurons

1 Whole-cell patch clamp experiments were used to investigate the transduct ion mechanism of adenosine A,, receptors in modulating N-methyl-D-aspartate (NMDA)-induced currents in rat striatal brain slices. The A(2A) receptor a gonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-amidoadenosine (CGS 21680) i nhibited the NMDA, but not the (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazo lepropionic acid (AMPA) current in a subset of striatal neurons. 2 Lucifer yellow-filled pipettes in combination with immunostaining of A(2A ) receptors were used to identify CGS 21680-sensitive cells as typical medi um spiny striatal neurons. 3 Dibutyryl cyclic AMP and the protein kinase A activator Sp-cyclic AMPs, b ut not the protein kinase A inhibitors Rp-cyclic AMPS or PKI(14-24)amide ab olished the inhibitory effect of CGS 21680. The phospholipase C inhibitor U -73122, but not the inactive structural analogue U-73343 also interfered wi th CGS 21680. The activation of protein kinase C by phorbol 12-myristate 13 -acetate or the blockade of this enzyme by staurosporine did. not alter the effect of CGS 21680. Heparin, an antagonist of inositol 1,4,5-trisphosphat e (InsP(3)) and a more efficient buffering of intracellular Ca2+ by BAPTA i nstead of EGTA in the pipette solution, abolished the CGS 21680-induced inh ibition. 4 The calmodulin antagonist W-7 and cytochalasin B which enhances actin dep olymerization also prevented the effect of CGS 21680; the calmodulin kinase II inhibitors CaM kinase II(281 - 309) and KN-93 but not the inactive stru ctural analogue KN-92 were also effective. The calcineurin inhibitor deltam ethrin did not interfere with CGS 21680. 5 It is suggested that the transduction mechanism of A(2A) receptors to inh ibit NMDA receptor channels is the phospholipase C/InsP(3)/calmodulin and c almodulin kinase II pathway. The adenylate cyclase/protein kinase A and pho spholipase C/protein kinase C pathways do not appear to be involved.