In adult atrial myocytes, spontaneous or caffeine- induced Ca²⁺ release from the SR induces inward currents carried by NCX, which are superimposed by large single channel current fluctuations (LCC, Mechmann,M. & Pott, L.1986. Nature 319, 579-599). The unusual low density (<10 per cell ), the large unitary conductance (280 pS), and the poor cation selectivity argue against a role of LCC in normal electrophysiology of cardiac myocytes. Moreover its molecular nature is controversial. Connexin-hemichannels, ryanodine receptors and polycystin-2 channels have been discussed as candidates. In cultured atrial and ventricular myocytes of adult rats mean LCC activity (n x p_o) is reduced by more than 90% after >= 5 d as compared to cells measured within 48 h after isolation. This is paralleled by a loss in expression of Pannnexin1 (Panx1) as demonstrated by immunocytochemistry. Infection of myocytes with a Panx1-encoding adenovirus rescued LCC-activity at >= 5d in vitro. LCC activity was reduced by carbenoxolone, probenicid, and ATP >= 1 mM, whereas lower concentrations of ATP (100 mM) increased channel activity. This pharmacological profile corresponds to that of currents carried by Panx1 e.g. in Xenopus oocytes and HEK cells. Pannexin channels and LCC-activity are mechanosensitive. A recent study suggests that stretch activation of these channels might induce cellular ATP release which in turn results in activation of purinergic receptors (Buvinic, S. et al. 2009, DOI 10.1074/jbc.M109.057315) Ca²⁺-influx through ATP-activated purinergic P_2X receptors might contribute to Ca²⁺-signalling in cardiac myocytes.