TASK-3, a Novel Tandem Pore Domain Acid-sensitive K+Channel

Abstract

Tandem pore domain acid-sensitive K ؉ channel 3 (TASK-3) is a new member of the tandem pore domain potassium channel family. A cDNA encoding a 365-amino acid polypeptide with four putative transmembrane segments and two pore regions was isolated from guinea pig brain. An orthologous sequence was cloned from a human genomic library. Although TASK-3 is 62% identical to TASK-1, the cytosolic C-terminal sequence is only weakly conserved. Analysis of the gene structure identified an intron within the conserved GYG motif of the first pore region. Reverse transcriptase-polymerase chain reaction analysis showed strong expression in brain but very weak mRNA levels in other tissues. Cellattached patch-clamp recordings of TASK-3 expressed in HEK293 cells showed that the single channel currentvoltage relation was inwardly rectifying, and open probability increased markedly with depolarization. Removal of external divalent cations increased the mean single channel current measured at ؊100 mV from ؊2.3 to ؊5.8 pA. Expression of TASK-3 in Xenopus oocytes revealed an outwardly rectifying K ؉ current that was strongly decreased in the presence of lower extracellular pH. Substitution of the histidine residue His-98 by asparagine or tyrosine abolished pH sensitivity. This histidine, which is located at the outer part of the pore adjacent to the selectivity filter, may be an essential component of the extracellular pH sensor.

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.…”

“…SUP-9 is 49 -51% identical in amino acid sequence to human TASK-1(KCNK3), TASK-3(KCNK9), and TASK-5(KCNK15) channels as well as to two predicted Drosophila proteins. Mammalian TASK-1 and TASK-3 behave as pH-sensitive background K ϩ channels when expressed heterologously in mammalian cell lines (Duprat et al, 1997;Kim et al, 1998;Leonoudakis et al, 1998;Rajan et al, 2000), whereas the properties of TASK-5 channels remain unknown. All other identified human two-pore K ϩ channels, such as TREK-1(KCNK2), share Ͻ30% amino acid identity with SUP-9.…”

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

“…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.…”

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

“…Adding to the complexity of KCNK3 regulation, the closely related acid‐sensitive KCNK9 channel dimerizes with KCNK3, forming KCNK9‐KCNK3 heterodimeric channels in tissues where both channels are expressed 11, 12, 13, 14, 15. KCNK9 is more maximally activated at pH 7.4 than KCNK3 16, 17. The channels are co‐expressed in a variety of tissues, promoting tissue‐specific diversity of channel function.…”