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.