Preferred Formation of Heteromeric Channels between Coexpressed SK1 and IKCa Channel Subunits Provides a Unique Pharmacological Profile of Ca 2+ -Activated Potassium Channels

Three small conductance calcium-activated potassium channel (SK) 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 intermediate conductance calcium-activated potassium chan...

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Bibliographic Details
Published in:	Molecular pharmacology Vol. 96; no. 1; p. 115
Main Authors:	Higham, James, Sahu, Giriraj, Wazen, Rima-Marie, Colarusso, Pina, Gregorie, Alice, Harvey, Bartholomew S J, Goudswaard, Lucy, Varley, Gemma, Sheppard, David N, Turner, Ray W, Marrion, Neil V
Format:	Journal Article
Language:	English
Published:	United States 01-07-2019
Subjects:	Cell Line Fluorescence Resonance Energy Transfer HEK293 Cells Humans Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism Microscopy Multiprotein Complexes - metabolism Small-Conductance Calcium-Activated Potassium Channels - metabolism Stochastic Processes
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Summary:	Three small conductance calcium-activated potassium channel (SK) 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 intermediate conductance calcium-activated potassium channel (IKCa) 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. Stochastic optical reconstruction microscopy super-resolution microscopy revealed that coexpressed IKCa and SK1 channel subunits were closely associated, a finding substantiated by measurement of fluorescence resonance energy transfer between coexpressed 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 coexpression 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.
ISSN:	1521-0111
DOI:	10.1124/mol.118.115634