TASK-5, a novel member of the tandem pore K + channel family

Abstract

We have cloned a novel member of the tandem pore K+ channel family from human brain cDNA. The novel cDNA encodes a 330-residue polypeptide of predicted molecular mass 36 kDa. We have named the channel TASK-5 owing to its sequence homology with TASK-1 and TASK-3. TASK-5 mRNA is expressed in pancreas, liver, kidney, lung, ovary, testis and heart. However, expression of TASK-5 in heterologous systems failed to elicit ionic currents. Removal of a putative endoplasmic reticulum retention sequence did not alter this finding and the distribution of channel proteins in HEK293 cells was similar for both TASK-1 and TASK-5. We tested whether TASK-5 could form heteromers with TASK-1. We show a mutant form of TASK-1 (H98N) to have a radically reduced sensitivity to acidification. Proton sensitivity could be rescued by injecting equimolar amounts of wild-type and mutant TASK-1 cRNA into Xenopus oocytes; the effect was that expected if half the channels formed are heteromers. Co-expression of TASK-5 with TASK-1 H98N does not affect the proton sensitivity of mutant TASK-1; thus TASK-5 appears not to form heteromers with TASK-1. Nonetheless, TASK-5 may require some other, unidentified partner subunit to form functional channels in the plasma membrane or it may form a channel in an intracellular organelle.

The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains

“…It is well established that replacement of His98 weakens the pH sensitivity of TASK-1 and TASK-3 and this residue is thought to act as proton sensor [1,26,33,38,44]. However, substitution of H98 is not the only replacement of an amino acid residue that causes loss or reduction in pH sensitivity.…”

“…The domain was connected to the top of the channel based on four restraints: (1) The N terminus of the first helix of the linker was positioned in close proximity to the C terminus of the M1 helix, as they are separated by at most three residues; (2) the second helix was angled so that its C-terminal end was not too far from the N-terminal end of the P1 pore helix; (3) N53 was mutated to Cys, and a disulphide bridge was modelled between the substituted Cys residues; and (4) secondary structure restraints were imposed to retain the two predicted helices. Once the initial model was created, the Cys residues were mutated back to Asn.…”

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

“…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. However, sequence homology and similarities in topology with other K 2p channel family members strongly suggests conserved function.…”

Deafness associated changes in expression of two-pore domain potassium channels in the rat cochlear nucleus

“…The subunits are divided into six groups or classes based on different sensitivities to various modulators. To date, attempts at functional expression (Ashmole et al, 2001;Rajan et al, 2001) of TASK-5 and THIK-2 have failed so their biophysical properties are undefined. However, sequence homology and similarities in topology with other family members strongly suggests conserved function.…”