Functional histamine H-3 and adenosine A(2A) receptor heteromers in recombinant cells and rat striatum
Por:
Márquez-Gómez R., Robins M.T., Gutiérrez-Rodelo C., Arias J.-M., Olivares-Reyes J.-A., Rijn R.M., Arias-Montaño J.-A.
Publicada:
1 mar 2018
Categoría:
Pharmacology
Resumen:
In the striatum, histamine H-3 receptors (H(3)Rs) are co-expressed with
adenosine A(2A) receptors (A(2A)Rs) in the cortico-striatal
glutamatergic afferents and the GABAergic medium-sized spiny neurons
that originate the indirect pathway of the basal ganglia. This location
allows H(3)Rs and A(2A)Rs to regulate the striatal GABAergic and
glutamatergic transmission. However, whether these receptors can
physically interact has not yet been assessed. To test this hypothesis,
a heteromer-selective in vitro assay was used to detect functional
complementation between a chimeric A(2A) R-302-G alpha(qi4) and
wild-type H(3)Rs in transfected HEK-293T cells. H3R activation with the
agonist RAMH resulted in Ca2+ mobilization (pEC(50) 7.31 +/- 0.23;
maximal stimulation, Emax 449 +/- 25% of basal) indicative of receptor
heterodimerization. Functional H3R-A(2A)R heteromers were confirmed by
co-immunoprecipitation and observations of differential CAMP signaling
when both receptors were co-expressed in the same cells. In membranes
from rat striatal synaptosomes, H3R activation decreased A(2A)R affinity
for the agonist CGS-21680 (pKi values 8.10 +/- 0.04 and 7.70 +/- 0.04).
Moreover, H(3)Rs and A(2A)Rs co-immunoprecipitated in protein extracts
from striatal synaptosomes. These results support the existence of a
H3R-A(2A)R heteromer with possible physiological implications for the
modulation of the intra-striatal transmission. (C) 2017 Elsevier Ltd.
All rights reserved.
Filiaciones:
Márquez-Gómez R.:
Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
Robins M.T.:
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, USA
Gutiérrez-Rodelo C.:
Departamento de Bioquímica, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
Arias J.-M.:
Programa de Neurociencias-UIICSE, Facultad de Estudios Superiores Iztacala, UNAM, Av. de los Barrios 1, Los Reyes Iztacala, 54090 Estado de México, Mexico
Olivares-Reyes J.-A.:
Departamento de Bioquímica, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
Rijn R.M.:
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, USA
Arias-Montaño J.-A.:
Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
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