Adenosine A2A and histamine H3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [3H]-GABA release from rat striato-pallidal terminals
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We previously reported that the activation of histamine H3 receptors (H3Rs) selectively counteracts the facilitatory action of adenosine A2A receptors (A2ARs) on GABA release from rat globus pallidus (GP) isolated nerve terminals (synaptosomes). In this work, we examined the mechanisms likely to underlie this functional interaction. Three possibilities were explored: (a) changes in receptor affinity for agonists induced by physical A2AR/H3R interaction, (b) opposite actions of A2ARs and H3Rs on depolarization-induced Ca2+ entry, and (c) an A2AR/H3R interaction at the level of adenosine 3′,5′-cyclic monophosphate (cAMP) formation. In GP synaptosomal membranes, H3R activation with immepip reduced A2AR affinity for the agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680) (Ki control 4.53 nM; + immepip 9.32 nM), whereas A2AR activation increased H3R affinity for immepip (Ki control 0.63 nM; + CGS-21680 0.26 nM). Neither A2AR activation nor H3R stimulation modified calcium entry through voltage-gated calcium channels in GP synaptosomes, as evaluated by microfluorometry. A2AR-mediated facilitation of depolarization-evoked [2,3-3H]-γ-aminobutyric acid ([3H]-GABA) release from GP synaptosomes (130.4 ± 3.6% of control values) was prevented by the PKA inhibitor H-89 and mimicked by the adenylyl cyclase activator forskolin or by 8-Bromo-cAMP, a membrane permeant cAMP analogue (169.5 ± 17.3 and 149.5 ± 14.5% of controls). H3R activation failed to reduce the facilitation of [3H]-GABA release induced by 8-Bromo-cAMP. In GP slices, A2AR activation stimulated cAMP accumulation (290% of basal) and this effect was reduced (− 75%) by H3R activation. These results indicate that in striato-pallidal nerve terminals, A2ARs and H3Rs interact at the level of cAMP formation to modulate PKA activity and thus GABA release.
KeywordsAdenosine A2A receptor Histamine Histamine H3 receptor Globus pallidus Basal ganglia GABA release
Adenosine A2A receptor
Histamine H3 receptor
G.-E.M.-F. and N.R.R. held Conacyt pre-doctoral scholarships.
G.-E.M.-F., E.J.G., and J.-A.A.-M. designed the study. G.-E.M.-F., J.E.-S., R.G.-P., U.G.-H., and N.R.-R. conducted experiments. G.-E.M.-F. and J.-A.A.-M. performed data analysis. G.-E.M.-F. and J.-A.A.-M. wrote the manuscript.
This study was supported by Cinvestav and Conacyt (grant 220448 to J.-A.A.-M.).
Compliance with ethical standards
Conflict of interest
The authors declare they do not have any actual or potential conflict of interest.
All procedures were approved by the Cinvestav Animal Care Committee and followed the guidelines for the care and use of laboratory animals issued by the National Institutes of Health (NIH Publications No. 8023, revised 1978) and the Mexican Council for Animal Care (NOM-062-ZOO-1999).
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