Two-pore domain potassium channels enable action potential generation in the absence of voltage-gated potassium channels

In this study, we explored the possibility that two-pore domain potassium (K(2P)) channels are sufficient to support action potential (AP) generation in the absence of conventional voltage-gated potassium (K(V)) channels. Hodgkin–Huxley parameters were used to mimic the presence of voltage-gated sodium (Na(V)) channels in HEK-293 cells. Recombinant expression of either TREK-1 or TASK-3 channels was then used to generate a hyperpolarised resting membrane potential (RMP) leading to the characteristic non-linear current–voltage relationship expected of a K(2P)-mediated conductance. During conductance simulation experiments, both TASK-3 and TREK-1 channels were able to repolarise the membrane once AP threshold was reached, and at physiologically relevant current densities, this K(2P)-mediated conductance supported sustained AP firing. Moreover, the magnitude of the conductance correlated with the speed of the AP rise in a manner predicted from our computational studies. We discuss the physiological impact of axonal K(2P) channels and speculate on the possible clinical relevance of K(2P) channel modulation when considering the actions of general and local anaesthetics.