The two-pore-domain potassium channels TASK-1 and TASK-3 are robustly inhibited by activation of receptors coupled to the Gaq subgroup of G-proteins, but the signal transduction pathway is still unclear.

We have studied the mechanisms by which endothelin receptors inhibit the current carried by TASK-1 channels (I_TASK) in isolated rat ventricular cardiomyocytes. Patch clamp measurements were carried out in isolated rat cardiomyocytes and in a mammalian cell line (CHO cells) transfected with TASK-1 and the endothelin A (ET_A) receptor. The ability of the ETA receptor to activate phospholipase C (PLC)-mediated signalling pathways was examined using TIRF measurements with a fluorescent probe for PLC activity.

I_TASK in cardiomyocytes, identified by sensitivity to extracellular acidification and the TASK-1 blocker A293, was completely inhibited by application of 100 nM endothelin-1. The inhibitory effect of endothelin-1 on I_TASK was not affected by inhibitors of protein kinase C (PKC) but was strongly reduced by the inhibitor of PLC, U73122. The PLC inhibitor effectively blocked PLC-mediated signalling as verified with a fluorescent probe for PI(4,5)P₂ hydrolysis. U73343, an inactive analogue of U73122, did not inhibit the effects of endothelin-1 on PI(4,5)P₂ hydrolysis and on I_TASK.

Our results show that in rat cardiomyocytes I_TASK is controlled by endothelin receptors and suggest that inhibition of TASK-1 by endothelin receptors is mediated by activation of PLC. However, previous work ruled out depletion of PI(4,5)P₂ and our present results rule out activation of PKC as the downstream mechanism mediating Gaq-dependent inhibition of TASK-1 channels.