SAT-038 Physiology of Mice Lacking All Four Adenosine Receptors

Abstract

The importance of multiple adenosine receptors (AR) and the role of adenosine signaling in normal physiology, as opposed to danger/damage situations, are unclear. We generated mice (QKO) lacking all four AR, Adora1-/-;Adora2a-/-;Adora2b-/-;Adora3-/-, to enable investigation of the AR-dependence of physiologic processes. The QKO mice bred normally and had similar body temperature regulation as controls, including diurnal variation, fasting-induced torpor, and response to environmental stimuli. Pharmacologic doses of adenosine agonists cause profound hypothermia via each of the four AR. We hypothesized that uptake and phosphorylation of adenosine might also trigger hypothermia by additional mechanisms, such as activation of adenosine monophosphate-activated protein kinase (AMPK). However, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent, ‘energy depletion’ signals do not cause adenosine-induced hypothermia. AMP-induced hypothermia was attenuated in QKO mice, demonstrating a role for both AR-dependent and AR-independent mechanisms in this process. In contrast, the hypothermias elicited by adenosine kinase inhibition (using A-134974), inosine, and uridine each require AR, as all were abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport, increasing local extracellular adenosine levels. The physiology of the QKO mice replicates that of the individual knockout mice, without evidence for synergy, suggesting that the actions of the four AR are generally complementary. The relatively mild phenotype of the QKO mice supports the hypothesis that extracellular adenosine has less of a contribution to baseline physiology and is more important as a local signal of stress, damage, and/or danger.