Triggering of BDNF facilitatory action on neuromuscular transmission by adenosine A2A receptors.
Motor nerve terminals possess adenosine A(2A) receptors and brain derived neurotrophic factor (BDNF) TrkB receptors. In the present work we evaluated how BDNF actions on neuromuscular transmission would be influenced by adenosine A(2A) receptors activation. BDNF (20-100 ng/ml) on its own was devoid of effect on evoked endplate potentials (EPPs) recorded intracellularly from rat innervated diaphragms paralysed with tubocurarine. However, when BDNF was applied 45 min after a brief (2 min) depolarizing KCl (10 mM) pulse or when the adenosine A(2A) receptors were activated with CGS 21680 (10 nM), BDNF (20 ng/ml) increased EPPs amplitude without influencing the resting membrane potential of the muscle fibre. The action of BDNF was prevented by the adenosine A(2A) receptor antagonist, ZM 241385 (50 nM) as well as by the TrkB receptor phosphorylation inhibitor, K252a (200 nM). The PKA inhibitor, H-89 (1 microM), prevented the excitatory effect of CGS 21680 (10 nM) on EPPs as well as prevented its ability to trigger a BDNF effect. The PLCgamma inhibitor, U73122 (5 microM), did not prevent the excitatory action of CGS 21680 (10 nM) on neuromuscular transmission, but abolished the action of BDNF in the presence of the A(2A) receptor agonist. The results suggest the following sequence of events in what concerns cooperativity between A(2A) receptors and TrkB receptors at the neuromuscular junction: A(2A) receptor activates the PKA pathway, which promotes the action of BDNF through TrkB receptors coupled to PLCgamma, leading to enhancement of neuromuscular transmission.
Pousinha
Paula A
PA
Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
Diogenes
Maria José
MJ
Ribeiro
Joaquim Alexandre
JA
Sebastião
Ana M
AM
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D058917:Adenosine A2 Receptor Antagonists; D019208:Brain-Derived Neurotrophic Factor; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine