Protein kinase A and Ca(v)1 (L-Type) channels are common targets to facilitatory adenosine A2A and muscarinic M1 receptors on rat motoneurons.
At the rat motor endplate, pre-synaptic facilitatory adenosine A2A and muscarinic M1 receptors are mutually exclusive. We investigated whether these receptors share a common intracellular signalling pathway. Suppression of McN-A-343-induced M1 facilitation of [3H]ACh release was partially recovered when CGS21680C (an A2A agonist) was combined with the cyclic AMP antagonist Rp-cAMPS. Forskolin, rolipram and 8-bromo-cyclic AMP mimicked CGS21680C blockade of M1 facilitation. Both Rp-cAMPs and nifedipine reduced augmentation of [3H]ACh release by McN-A-343 and CGS21680C. Activation of M1 and A2A 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 [3H]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 M1-induced PKC activation. In conclusion, competition of M1 and A2A 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.
Oliveira
Laura
L
Laboratório de Farmacologia, Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal.
Correia-de-Sá
Paulo
P
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects*; D005260:Female; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043705:Receptor, Adenosine A2A; D043643:Receptor, Muscarinic M1; C093712:Cacna1d protein, rat; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D017868:Cyclic AMP-Dependent Protein Kinases; D000109:Acetylcholine