ATP-Sensitive K + Channels Regulate the Concentrative Adenosine Transporter CNT2 following Activation by A 1 Adenosine Receptors

Author:

Duflot Sylvie1,Riera Bárbara1,Fernández-Veledo Sonia1,Casadó Vicent1,Norman Robert I.2,Casado F. Javier1,Lluís Carme1,Franco Rafael1,Pastor-Anglada Marçal1

Affiliation:

1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, E-08071 Barcelona, Spain

2. Division of Medicine and Therapeutics, Leicester Royal Infirmary, University of Leicester, Leicester LE1 7RH, United Kingdom

Abstract

ABSTRACT This study describes a novel mechanism of regulation of the high-affinity Na + -dependent adenosine transporter (CNT2) via the activation of A 1 adenosine receptors (A 1 R). This regulation is mediated by the activation of ATP-sensitive K + (K ATP ) channels. The high-affinity Na + -dependent adenosine transporter CNT2 and A 1 R are coexpressed in the basolateral domain of the rat hepatocyte plasma membrane and are colocalized in the rat hepatoma cell line FAO. The transient increase in CNT2-mediated transport activity triggered by (−)- N 6 -(2-phenylisopropyl)adenosine is fully inhibited by K ATP channel blockers and mimicked by a K ATP channel opener. A 1 R agonist activation of CNT2 occurs in both hepatocytes and FAO cells, which express Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B mRNA channel subunits. With the available antibodies against Kir6.X, SUR2A, and SUR2B, it is shown that all of these proteins colocalize with CNT2 and A 1 R in defined plasma membrane domains of FAO cells. The extent of the purinergic modulation of CNT2 is affected by the glucose concentration, a finding which indicates that glycemia and glucose metabolism may affect this cross-regulation among A 1 R, CNT2, and K ATP channels. These results also suggest that the activation of K ATP channels under metabolic stress can be mediated by the activation of A 1 R. Cell protection under these circumstances may be achieved by potentiation of the uptake of adenosine and its further metabolization to ATP. Mediation of purinergic responses and a connection between the intracellular energy status and the need for an exogenous adenosine supply are novel roles for K ATP channels.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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