TASK-1, a Two–Pore Domain K+ Channel, Is Modulated by Multiple Neurotransmitters in Motoneurons

Abstract

Inhibition of "leak" potassium (K+) channels is a widespread CNS mechanism by which transmitters induce slow excitation. We show that TASK-1, a two pore domain K+ channel, provides a prominent leak K+ current and target for neurotransmitter modulation in hypoglossal motoneurons (HMs). TASK-1 mRNA is present at high levels in motoneurons, including HMs, which express a K+ current with pH- and voltage-dependent properties virtually identical to those of the cloned channel. This pH-sensitive K+ channel was fully inhibited by serotonin, norepinephrine, substance P, thyrotropin-releasing hormone, and 3,5-dihydroxyphenylglycine, a group I metabotropic glutamate receptor agonist. The neurotransmitter effect was entirely reconstituted in HEK 293 cells coexpressing TASK-1 and the TRH-R1 receptor. Given its expression patterns and the widespread prevalence of this neuromodulatory mechanism, TASK-1 also likely supports this action in other CNS neurons.

sup-9, sup-10, andunc-93May Encode Components of a Two-Pore K+Channel that Coordinates Muscle Contraction inCaenorhabditis elegans

“…Mammalian TASK-1 and TASK-3 form a subfamily of two-pore K ϩ channels that are activated by high pH, volatile anesthetics, and neurotransmitters (Duprat et al, 1997;Leonoudakis et al, 1998;Patel et al, 1999;Kim et al, 2000;Millar et al, 2000;Rajan et al, 2000;Talley et al, 2000). Our findings indicate that UNC-93 and SUP-10 associate with a SUP-9 two-pore K ϩ channel and suggest that UNC-93 and SUP-10 may be regulatory subunits of this channel.…”

Deafness associated changes in two-pore domain potassium channels in the rat inferior colliculus

“…(Lesage and Lazdunski, 2000;Goldstein et al, 2001;Patel and Honore, 2001). In cerebellar granule cells (Millar et al, 2000) and cranial motoneurons (Talley et al, 2000) receptor-mediated inhibition of TASK-1 has been reported, which suggests an important role for the TASK family of K 2p channels in neuromodulation. Experiments testing functional expression of TASK-5 and THIK-2 have been unsuccessful to date (Ashmole et al, 2001;Rajan et al, 2001) and so their biophysical properties remain undefined.…”

“…TASK-5 has been placed into the category of acid-sensitive channels based on its sequence homology to TASK-1 and 3. In cerebellar granule cells (Millar et al, 2000) and cranial motoneurons (Talley et al, 2000) receptor-mediated inhibition of TASK-1 has been reported and TASK-3 is activated by depolarization and modulated by extracellular divalent cations (Rajan et al, 2000). TASK-5 might then be similarly sensitive to activity and neuromodulation.…”

TWIK-2, an Inactivating 2P Domain K+ Channel

“…TASK-1 has been recently proposed to encode the background K ϩ channel present in motoneurons, cerebellum granular cells, and type I carotid body cells (24 -26). In motoneurons and cerebellar neurons, the background TASK-1-like K ϩ current is reversibly inhibited by the activation of G q -coupled receptors, including the muscarinic receptor (25,26). In the chemoreceptor type I carotid body cells, TASK-1-like K ϩ channels are reversibly inhibited by acidosis and hypoxia (24,27).…”