ArticleThe Journal of general physiology2009
EF hands at the N-lobe of calmodulin are required for both SK channel gating and stable SK-calmodulin interaction.
Article in The Journal of general physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 61 citations in OpenAlex.
- Structural basis for the subtype-selective activation of KStructure (London, England : 1993) · 2026Article
- Structural basis for the subtype-selectivity of KNature communications · 2026Article
- 6,7-Dichloro-1H-indole-2,3-dione-3-oxime functions as a superagonist for the intermediate-conductance CaMolecular pharmacology · 2025Article
- Redox Regulation of KAntioxidants & redox signaling · 2024Review
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- Hydrophobic interactions between the HA helix and S4-S5 linker modulate apparent CaActa physiologica (Oxford, England) · 2021Article
- PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts.The Journal of physiology · 2020Article
- Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases.Frontiers in physiology · 2020Review
- Non-Additive Effects of Binding Site Mutations in Calmodulin.Biochemistry · 2019Article
- Functional Interaction among KInternational journal of molecular sciences · 2019Review
- A V-to-F substitution in SK2 channels causes CaScientific reports · 2018Article
- Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures.Science (New York, N.Y.) · 2018Article
- Coordination to lanthanide ions distorts binding site conformation in calmodulin.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Structure, Gating and Basic Functions of the Ca2+-activated K Channel of Intermediate Conductance.Current neuropharmacology · 2018Review
- Physiological Roles and Therapeutic Potential of CaFrontiers in molecular neuroscience · 2018Review
- Structural insights into the potency of SK channel positive modulators.Scientific reports · 2017Article
- Impact of Aging on Calcium Signaling and Membrane Potential in Endothelium of Resistance Arteries: A Role for Mitochondria.The journals of gerontology. Series A, Biological sciences and medical sciences · 2017Article
- CaChannels (Austin, Tex.) · 2017Article
- Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-Molecular pharmacology · 2017Article
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Small conductance calcium-activated potassium (SK) channels respond to intracellular Ca(2+) via constitutively associated calmodulin (CaM). Previous studies have proposed a modular design for the interaction between CaM and SK channels. The C-lobe and the linker of CaM are thought to regulate the constitutive binding, whereas the N-lobe binds Ca(2+) and gates SK channels. However, we found that coexpression of mutant CaM (E/Q) where the N-lobe has only one functional EF hand leads to rapid rundown of SK channel activity, which can be recovered with exogenously applied wild-type (WT), but not mutant, CaM. Our results suggest that the mutation at the N-lobe EF hand disrupts the stable interaction between CaM and SK channel subunits, such that mutant CaM dissociates from the channel complex when the inside of the membrane is exposed to CaM-free solution. The disruption of the stable interaction does not directly result from the loss of Ca(2+)-binding capacity because SK channels and WT CaM can stably interact in the absence of Ca(2+). These findings question a previous conclusion that CaM where the N-lobe has only one functional EF hand can stably support the gating of SK channels. They cannot be explained by the current model of modular interaction between CaM and SK channels, and they imply a role for N-lobe EF hand residues in binding to the channel subunits. Additionally, we found that a potent enhancer for SK channels, 3-oxime-6,7-dichloro-1H-indole-2,3-dione (NS309), enables the recovery of channel activity with CaM (E/Q), suggesting that NS309 stabilizes the interaction between CaM and SK channels. CaM (E/Q) can regulate Ca(2+)-dependent gating of SK channels in the presence of NS309, but with a lower apparent Ca(2+) affinity than WT CaM.
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