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Molecular and Cellular Biology, April 2004, p. 2710-2719, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2710-2719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ATP-Sensitive K⁺ Channels Regulate the Concentrative Adenosine Transporter CNT2 following Activation by A₁ Adenosine Receptors

Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, E-08071 Barcelona, Spain,¹ Division of Medicine and Therapeutics, Leicester Royal Infirmary, University of Leicester, Leicester LE1 7RH, United Kingdom²

Received 13 October 2003/ Returned for modification 11 November 2003/ Accepted 23 December 2003

This study describes a novel mechanism of regulation of the high-affinity Na⁺-dependent adenosine transporter (CNT2) via the activation of A₁ adenosine receptors (A₁R). This regulation is mediated by the activation of ATP-sensitive K⁺ (K_ATP) channels. The high-affinity Na⁺-dependent adenosine transporter CNT2 and A₁R 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 (-)-N⁶-(2-phenylisopropyl)adenosine is fully inhibited by K_ATP channel blockers and mimicked by a K_ATP channel opener. A₁R 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 A₁R 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 A₁R, 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 A₁R. 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.

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