TY - JOUR T1 - Preferred formation of heteromeric channels between co-expressed SK1 and IKCa channel subunits provides a unique pharmacological profile of Ca2+-activated potassium channels JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.115634 SP - mol.118.115634 AU - James Higham AU - Giriraj Sahu AU - Rima-Marie Wazen AU - Pina Colarusso AU - Alice Gregorie AU - Bartholomew S. J. Harvey AU - Lucy Goudswaard AU - Gemma Varley AU - David N Sheppard AU - Ray W Turner AU - Neil V Marrion Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/05/02/mol.118.115634.abstract N2 - Three SK channel subunits have been cloned and found to preferentially form heteromeric channels when expressed in a heterologous expression system. The original cloning of the gene encoding the IKCa channel was termed SK4, because of the high homology between channel subtypes. Recent immunovisualization suggests that IKCa is expressed in the same subcellular compartments of some neurons as SK channel subunits. STORM super-resolution microscopy revealed that co-expressed IKCa and SK1 channel subunits were closely associated, a finding substantiated by measurement of FRET between co-expressed fluorophore-tagged subunits. Expression of homomeric SK1 channels produced current that displayed typical sensitivity to SK channel inhibitors, while expressed IKCa channel current was inhibited by known IKCa channel blockers. Expression of both SK1 and IKCa subunits gave a current that displayed no sensitivity to SK channel inhibitors and a decreased sensitivity to IKCa current inhibitors. Single channel recording indicated that co-expression of SK1 and IKCa subunits produced channels with properties intermediate between those observed for homomeric channels. These data indicate that SK1 and IKCa channel subunits preferentially combine to form heteromeric channels that display pharmacological and biophysical properties distinct from those seen with homomeric channels.SIGNIFICANCE STATEMENT Co-expression of hSK1 and hIKCa channel subunits produces current that displays an intermediate sensitivity to characterised IKCa current inhibitors, but is resistant to inhibitors of SK1-mediated current. These data show that SK1 and IKCa subunits preferentially combine to form heteromeric channels that have a unique pharmacology. ER -