title: The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function.
abstract: Channels of the two-pore domain potassium (K2P) family contain two pore domains rather than one and an unusually long pre-pore extracellular linker called the M1P1 loop. The TASK (TASK1, TASK3, and TASK5) subfamily of K2P channels is regulated by a number of different pharmacological and physiological mediators. At pH 7.4 TASK3 channels are selectively blocked by zinc in a manner that is both pH(o)- and [K](o)(-)dependent. Mutation of both the Glu-70 residue in the M1P1 loop and the His-98 residue in the pore region abolished block, suggesting the two residues may contribute to a zinc binding site. Mutation of one Glu-70 residue and one His-98 residue to cysteine in TASK3 fixed concatamer channels gave currents that were enhanced by dithiothreitol and then potently blocked by cadmium, suggesting that spontaneous disulfide bridges could be formed between these two residues. Swapping the M1P1 loops of TASK1 and TASK3 channels showed that the M1P1 loop is also involved in channel regulation by pH. Therefore, the TASK3 M1P1 loop lies close to the pore, regulating TASK3 channel activity.
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Clarke
authors.forename: Emma L
authors.initials: EL
authors.lastname: Veale
authors.forename: Ken
authors.initials: K
authors.lastname: Wyse
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.forename: Alistair
authors.initials: A
authors.lastname: Mathie
mesh_terms: D003545:Cysteine / Q000737:chemistry; D004594:Electrophysiology / Q000379:methods; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry
chemical_list: C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain; D018698:Glutamic Acid; D006639:Histidine; D015032:Zinc; D003545:Cysteine