Human adenosine deaminase as an allosteric modulator of human A1adenosine receptor: abolishment of negative cooperativity for [3H](R)-pia binding to the caudate nucleus

Autor: Jesús A. García-Sevilla, J. Javier Meana, Josefa Mallol, Michael S. Herhsfield, Antoni Cortés, Enric I. Canela, Carmen Lluis, Eduard Gracia, Rafael Franco, Vicent Casadó
Rok vydání: 2008
Předmět:
Zdroj: Journal of Neurochemistry. 107:161-170
ISSN: 1471-4159
0022-3042
DOI: 10.1111/j.1471-4159.2008.05602.x
Popis: It has been shown that adenosine deaminase (ADA; EC 3.5.4.4) behaves as an ecto-enzyme anchored to membrane proteins, among them A1 adenosine receptors (A1Rs). Bovine ADA interacts with A1Rs from many species and regulates agonists binding to receptors in an activity-independent form. However, it was not known whether human ADA exerted any effect on the agonist binding to human A1Rs, because of both technical difficulties in obtaining pure human ADA and tissues containing human A1Rs. In this study, human ADA was purified to homogeneity. Taking in consideration that A1Rs form homodimers and taking advantage of a new procedure to fit binding data to receptors dimers, which allows to calculate ligand dissociation constants and the degree of cooperativity between the two subunits in the dimer, here it is demonstrated that human ADA markedly enhances the agonist and antagonist affinity and abolishes the negative cooperativity on agonist binding to human striatal A1Rs. ADA also increases the ability of the agonist to decrease the forskolin-induced cAMP levels. The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A1R desensitization, binds to A1R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. The physiological role of the interaction is to make receptors more sensitive to adenosine. This powerful regulation has important implications for the physiology and pharmacology of neuronal A1Rs.
Databáze: OpenAIRE
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