Tetanic failure due to decreased endogenous adenosine A(2A) tonus operating neuronal Ca(v)1 (L-type) influx in Myasthenia gravis

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Noronha Matos, JB (Author) ICBAS; Morais, T (Author) Other; Trigo, D (Author) Other; Timoteo, MA (Author) Other; Magalhaes Cardoso, MT (Author) Other; oliveira, l (Author) ICBAS; Paulo Correia de Sá (Author) ICBAS

Journal

Title: Journal of Neurochemistry

Vol. 117

Pages: 797-811

ISSN: 0022-3042

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 29 Citations

Scopus - 30 Citations

Other information

Authenticus ID: P-002-R90

DOI: 10.1111/j.1471-4159.2011.07216.x

Abstract (EN): P>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 Ca2+ 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 [3H]acetylcholine (ACh) release by the Ca(V)2.1 (P/Q) channel blocker, omega-Agatoxin IVA (100 nM), in TIMG rats had a higher magnitude than that observed with the Ca(V)1 (L) channel blocker, nifedipine (1 mu M). Adenosine deaminase (0.5 U/mL) and the A(2A) receptor antagonist, ZM 241385 (50 nM), decreased [3H]ACh release by a similar amount in control rats, but their effects were smaller in magnitude in myasthenic animals. The adenosine precursor, AMP (100 mu M), increased (similar to 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 mu M) 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15