title: Tetanic failure due to decreased endogenous adenosine A(2A) tonus operating neuronal Ca(v) 1 (L-type) influx in Myasthenia gravis.
abstract: In healthy motor endplates, tetanic depression is overcome by tonic adenosine A(2A) -receptor-mediated facilitation of transmitter release. The A(2A) receptor operates a coordinated shift from fast-desensitizing Ca(v) 2.1 (P/Q) calcium influx to long-lasting Ca(V) 1 (L) channels on motor nerve terminals. This study aimed at investigating whether A(2A) receptors-operated Ca(2+) influx via Ca(V) 1 (L)-type channels contribute to sustain acetylcholine release evoked by 50 Hz-bursts in toxin-induced Myasthenia gravis (TIMG) rats. In contrast to control animals, inhibition of [(3) H]acetylcholine (ACh) release by the Ca(V) 2.1 (P/Q) channel blocker, ω-Agatoxin IVA (100 nM), in TIMG rats had a higher magnitude than that observed with the Ca(V) 1 (L) channel blocker, nifedipine (1 μM). Adenosine deaminase (0.5 U/mL) and the A(2A) receptor antagonist, ZM 241385 (50 nM), decreased [(3) H]ACh release by a similar amount in control rats, but their effects were smaller in magnitude in myasthenic animals. The adenosine precursor, AMP (100 μM), increased (~40%) ACh release in both control and TIMG animals. Blockade of A(2A) , but not of A(1) , receptors prevented AMP-induced facilitation of transmitter release; nifedipine (1 μM) mimicked the effect of the A(2A) receptor antagonist. Video-microscopy studies designed to measure real-time transmitter exocytosis using the FM4-64 fluorescent dye fully supported radiochemical data. Thus, impairment of the adaptive shift from Ca(V) 2.1 (P/Q) to Ca(V) 1 (L) channels may contribute to tetanic failure in myasthenic rats. This parallels the reduction of adenosine A(2A) receptor tonus in TIMG animals, which might be restored by exogenous application of AMP.
authors.affiliation: Laboratório de Farmacologia e Neurobiologia/UMIB, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, L. Prof. Abel Salazar 2, Porto, Portugal.
authors.forename: J B
authors.initials: JB
authors.lastname: Noronha-Matos
authors.forename: T
authors.initials: T
authors.lastname: Morais
authors.forename: D
authors.initials: D
authors.lastname: Trigo
authors.forename: M A
authors.initials: MA
authors.lastname: Timóteo
authors.forename: M T
authors.initials: MT
authors.lastname: Magalhães-Cardoso
authors.forename: L
authors.initials: L
authors.lastname: Oliveira
authors.forename: P
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002038:Bungarotoxins; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D005456:Fluorescent Dyes; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018715:Microscopy, Video; D009046:Motor Neurons / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009157:Myasthenia Gravis / Q000139:chemically induced / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010791:Phrenic Nerve / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D012235:Rhodamines
chemical_list: D000109:Acetylcholine; D000241:Adenosine; D000255:Adenosine Triphosphate; D002038:Bungarotoxins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D002800:Cholinesterase Inhibitors; D005456:Fluorescent Dyes; D018377:Neurotransmitter Agents; D043705:Receptor, Adenosine A2A; D012235:Rhodamines; C005358:tetramethylrhodamine