Background and purpose: Diadenosine polyphosphates are normally present in cells at low levels, but significant increases in concentrations can occur during cellular stress. The aim of this study was to investigate the effects of diadenosine pentaphosphate (Ap5A) and an oxidized analogue, oAp5A on the gating of sheep cardiac ryanodine receptors (RyR2). Experimental approach: RyR2 channel function was monitored after incorporation into planar bilayers under voltage-clamp conditions. Key results: With10 mmol·L -1 cytosolic Ca 2+, a significant 'hump' or plateau at the base of the dose-response relationship to Ap5A was revealed. Open probability (Po) was significantly increased to a plateau of approximately 0.2 in the concentration range 100 pmol·L ). Perfusion experiments suggest that oAp5A and Ap5A dissociate slowly from their binding sites on RyR2. Conclusions and implications:The ability of Ap5A compounds to increase Po even in the presence of ATP and their slow dissociation from the channel may enable these compounds to act as physiological regulators of RyR2, particularly under conditions of cellular stress.

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