Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact

A distinct gene family of widely distributed and well-modulated two-pore-domain background potassium (K-2P) channels establish resting membrane potential and cell excitability. By using new mouse models in which K-2P-channel genes are deleted, the contributions of these channels to important physiological functions are now being revealed. Here, we highlight results of recent studies using mice deleted for K-2P-channel sub-units that uncover physiological functions of these channels, mostly those of the TASK and TREK subgroup. Consistent with activation of these K-2P channels by volatile anesthetics, TASK-1, TASK-3 and TREK-1 contribute to anesthetic-induced hypnosis and immobilization. The acid-sensitive TASK channels are not required for brainstem control of breathing by CO2 or pH, despite widespread expression in respiratory-related neurons. TASK channels are necessary, however, for homeostatic regulation of adrenal aldosterone secretion. The heat-, stretch- and lipid-activated TREK-1 channels contribute to temperature and mechanical pain sensation, neuro-protection by polyunsaturated fatty acids and, unexpectedly, mood regulation. The alkaline-activated TASK-2 channel is necessary for HCO3- reabsorption and osmotic volume regulation in kidney proximal tubule cells. Development of compounds that selectively modulate K-2P channels is crucial for verifying these results and assessing the efficacy of therapies targeting these interesting channels.