A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons

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Abstract
Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a “standing-outward” K+ current, or IKSO, which does not inactivate. It is active at the resting potential of CGNs, and blocking IKSO leads to cell depolarization. IKSO is blocked by Ba2+ ions and is regulated by activation of muscarinic M3 receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IKSO is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IKSO has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M3 muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.