Preferred Formation of Heteromeric Channels between Coexpressed SK1 and IKCa Channel Subunits Provides a Unique Pharmacological Profile of Ca²⁺-Activated Potassium Channels

Abstract

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.

Noradrenaline Release from Locus Coeruleus Terminals in the Hippocampus Enhances Excitation-Spike Coupling in CA1 Pyramidal Neurons Via β-Adrenoceptors

“…2012 ; King et al. 2015 ; Higham et al. 2019 ) it is plausible that these channels are located in the more distal dendrites only accessible to exogenous NA acting on β-ARs.…”

Ca2+-activated KCa3.1 potassium channels contribute to the slow afterhyperpolarization in L5 neocortical pyramidal neurons

“…Our experiments demonstrated SK- and KCa3.1-related conductances, which were blocked in sAHP+ cells by apamin and TRAM-34 independently. However, a recent study 26 demonstrated that co-expression of SK1 and KCa3.1 subunits can produce heteromeric channels with intermediate properties, sensitive to TRAM-34 but without apamin sensitivity. Thus, the localization of KCa3.1 subunits in sAHP+ cells may affect the expression of their apamin-sensitive SK currents.…”

Junctophilin Proteins Tether a Cav1-RyR2-KCa3.1 Tripartite Complex to Regulate Neuronal Excitability

“…The amplified KCa3.1 PCR product was inserted into pCMV6-entry vector (Oregene, USA) in frame to the myc polypeptide sequence to create the KCa3.1-myc construct, where the myc tag was placed at the C terminus of KCa3.1. KCa3.1 was also tagged with eGFP or mKate at the C terminus without altering functional properties as previously reported (Higham et al, 2019;Sahu et al, 2017). In the case of the RyR2-GFP construct, the eGFP sequence was attached to the extracellular loop at amino acid position D4365, previously established to have no effect on RyR2 function (Liu et al, 2002).…”