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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 7, 2004; DOI: 10.1124/jpet.103.061564

0022-3565/04/3083-1148-1157$20.00
JPET 308:1148-1157, 2004
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NEUROPHARMACOLOGY

GABA Modulates Presynaptic Signalling Mediated by Dinucleotides on Rat Synaptic Terminals

R. Gómez-Villafuertes, J. Pintor, J. Gualix, and M. T. Miras-Portugal

Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain

Diadenosine pentaphosphate (Ap5A) elicits Ca2+ transients in isolated rat midbrain synaptic terminals acting through specific ionotropic dinucleotide receptors. The activation of GABAB receptors by baclofen changes the sigmoidal concentration-response curve for Ap5A (EC50 = 44 µM) into biphasic curves. Thus, when GABAB receptors are activated, the curve shows a high-affinity component in the picomolar range (EC50 = 77 pM) and a low-affinity component in the micromolar range (EC50 = 17 µM). In addition, in the presence of GABA or baclofen, Ap5A calcium responses are increased up to 50% over the control values. Saclofen, a specific antagonist of GABAB receptors, blocks the potentiatory effect of baclofen. As occurs with Ap5A, GABAB receptors are also capable to modulate diguanosine pentaphosphate (Gp5G)-induced calcium responses. The combination of immunocytochemical and microfluorimetric techniques carried out on single synaptic terminals have shown that in the presence of baclofen, 64% of the terminals responding to 100 µM Ap5A are also able to respond to 100 nM Ap5A. This value is close to the percentage of synaptic terminals responding to Ap5A and labeled with the anti-GABAB receptor antibody (69%). The activity of cyclic AMP-dependent protein kinase (PKA) seems to be involved in the potentiatory effect of GABAB receptors on Ap5A calcium responses, because PKA activation by forskolin or dibutiryl cyclic AMP blocks the potentiatory effect of baclofen, whereas PKA inhibition facilitates calcium signaling mediated by Ap5A. These results demonstrate that the activation of presynaptic GABAB receptors is able to modulate dinucleotide responses in synaptic terminals.

Received for publication October 14, 2003
Accepted November 25, 2003.

Address correspondence to: Dr. M. T. Miras-Portugal, Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, Av. Puerta de Hierro s/n, 28040 Madrid, Spain. E-mail: mtmiras{at}vet.ucm.es






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