Protein kinase A and Ca(v)1 (L-type) channels are common targets to facilitatory adenosine A(2A) and muscarinic M-1 receptors on rat motoneurons

At the rat motor endplate, pre-synaptic facilitatory adenosine A(2A) and muscarinic M-1 receptors are mutually exclusive. We investigated whether these receptors share a common intracellular signalling pathway. Suppression of McN-A-343-induced M-1 facilitation of [H-3] ACh release was partially recovered when CGS21680C ( an A(2A) agonist) was combined with the cyclic AMP antagonist Rp- cAMPS. Forskolin, rolipram and 8-bromo-cyclic AMP mimicked CGS21680C blockade of M 1 facilitation. Both Rp-cAMPs and nifedipine reduced augmentation of [H-3] ACh release by McN-A-343 and CGS21680C. Activation of M-1 and A(2A) receptors enhanced Ca2+ recruitment through nifedipine-sensitive channels. Nifedipine inhibition revealed by McN-A-343 was prevented by chelerythrine (a PKC inhibitor) and Rp-cAMPS, suggesting that Ca(v)1 (L-type) channels phosphorylation by PKA and PKC is required. Rp- cAMPS inhibited [H-3] ACh release in the presence of phorbol 12-myristate 13-acetate, but PKC inhibition by chelerythrine had no effect on release in the presence of 8-bromo-cyclic AMP. This suggests that the involvement of PKA may be secondary to M-1-induced PKC activation. In conclusion, competition of M-1 and A(2A) receptors to facilitate ACh release from motoneurons may occur by signal convergence to a common pathway involving PKA activation and Ca2+ influx through Ca(v)1 (L-type) channels. Copyright (C) 2005 S. Karger AG, Basel.