Diadenosine polyphosphate-induced inhibition of cardiac KATP channels: operative state-dependent regulation by a...

It has been proposed that the regulatory action of mononucleotides, such as ATP and UDP, on cardiac ATP-sensitive K+ (KATP) channels is determined by the state of the channel. Recently, dinucleotides, such as diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A), have been recognized as novel intracellular ligands of cardiac KATP channels. However, it is not known whether the state of KATP channels also determines the response of the channel to dinucleotides. Therefore, we examined the action of diadenosine polyphosphates on KATP channel activity during different operative channel states, using the inside-out patch clamp technique applied to patches excised from guinea-pig ventricular myocytes. Spontaneous openings of KATP channels (or operative condition 1) were inhibited by Ap4A and Ap5A. Addition of UDP, which on its own did not affect spontaneous openings of KATP channels, prevented Ap4A and Ap5A to inhibit spontaneous KATP channel activity. In contrast, following "run-down" of spontaneous channel activity, UDP induced KATP channel openings (or operative condition 2), but could no longer antagonize the inhibitory effect of Ap4A and Ap5A. We conclude that the inhibitory action of diadenosine polyphosphates on KATP channels can be blocked by UDP only when KATP channels are in operative condition 1, but not in operative condition 2. Thus, the operative condition of KATP channels determines the UDP-mediated regulation of the diadenosine polyphosphate-dependent inhibitory channel gating. This finding further suggests that the operative state of the cardiac KATP channel protein is a critical determinant of the regulatory action of an intracellular ligand.