Adenosine A 2A and histamine H 3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [ 3 H]-GABA release from rat striato-pallidal terminals

Purinergic signalling

article

Guadalupe-Elide Morales-Figueroa¹  Nayeli Rivera-Ramírez¹  Raúl González-Pantoja¹  Juan Escamilla-Sánchez¹  Ubaldo García-Hernández¹  Emilio J. Galván²  José-Antonio Arias-Montaño¹ 

[1]Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN

[2]Departamento de Farmacobiología

关键词: Adenosine A2A receptor;    Histamine;    Histamine H3 receptor;    Globus pallidus;    Basal ganglia;    GABA release;   

DOI  :  10.1007/s11302-018-9638-z

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY