Expression and Impact of Adenosine A 3 Receptors on Calcium Homeostasis in Human Right Atrium.

Increased adenosine A 2A receptor (A 2A R) expression and activation underlies a higher incidence of spontaneous calcium release in atrial fibrillation (AF). Adenosine A 3 receptors (A 3 R) could counteract excessive A 2A R activation, but their functional role in the atrium remains elusive, and we therefore aimed to address the impact of A 3 Rs on intracellular calcium homeostasis. For this purpose, we analyzed right atrial samples or myocytes from 53 patients without AF, using quantitative PCR, patch-clamp technique, immunofluorescent labeling or confocal calcium imaging. A 3 R mRNA accounted for 9% and A 2A R mRNA for 32%. At baseline, A 3 R inhibition increased the transient inward current (I TI ) frequency from 0.28 to 0.81 events/min ( p < 0.05). Simultaneous stimulation of A 2A Rs and A 3 Rs increased the calcium spark frequency seven-fold ( p < 0.001) and the I TI frequency from 0.14 to 0.64 events/min ( p < 0.05). Subsequent A 3 R inhibition caused a strong additional increase in the I TI frequency (to 2.04 events/min; p < 0.01) and increased phosphorylation at s2808 1.7-fold ( p < 0.001). These pharmacological treatments had no significant effects on L-type calcium current density or sarcoplasmic reticulum calcium load. In conclusion, A 3 Rs are expressed and blunt spontaneous calcium release at baseline and upon A 2A R-stimulation in human atrial myocytes, pointing to A 3 R activation as a means to attenuate physiological and pathological elevations of spontaneous calcium release events.