ArticlePloS one2014
Polarized axonal surface expression of neuronal KCNQ potassium channels is regulated by calmodulin interaction with KCNQ2 subunit.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- Calmodulin assists during co-translational folding of the KProtein science : a publication of the Protein Society · 2026Article
- Coupling of functionality to trafficking of KCNQ2/3 potassium channels at the axon initial segment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Homeostatic regulation of extracellular signal-regulated kinase 1/2 activity and axonal KFrontiers in cellular neuroscience · 2022Article
- Heterozygous Deletion of Epilepsy GeneFrontiers in behavioral neuroscience · 2022Article
- Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of KProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Posttranscriptional modulation of KCNQ2 gene expression by the miR-106b microRNA family.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- PIPCommunications biology · 2021Article
- An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel.BMC biology · 2021Article
- Identifying mutation hotspots reveals pathogenetic mechanisms of KCNQ2 epileptic encephalopathy.Scientific reports · 2020Article
- Atomistic Insights of Calmodulin Gating of Complete Ion Channels.International journal of molecular sciences · 2020Review
- The Role of KFrontiers in physiology · 2020Review
- The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding.Frontiers in physiology · 2020Review
- Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment.Frontiers in cellular neuroscience · 2020Article
- TwoFrontiers in physiology · 2020Article
- The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement.International journal of molecular sciences · 2019Review
- The Crossroad of Ion Channels and Calmodulin in Disease.International journal of molecular sciences · 2019Review
- Reduced axonal surface expression and phosphoinositide sensitivity in KNeurobiology of disease · 2018Article
- Calmodulin: A Multitasking Protein in Kv7.2 Potassium Channel Functions.Biomolecules · 2018Review
- Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants.Channels (Austin, Tex.) · 2018Article
- M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KCNQ potassium channels composed of KCNQ2 and KCNQ3 subunits give rise to the M-current, a slow-activating and non-inactivating voltage-dependent potassium current that limits repetitive firing of action potentials. KCNQ channels are enriched at the surface of axons and axonal initial segments, the sites for action potential generation and modulation. Their enrichment at the axonal surface is impaired by mutations in KCNQ2 carboxy-terminal tail that cause benign familial neonatal convulsion and myokymia, suggesting that their correct surface distribution and density at the axon is crucial for control of neuronal excitability. However, the molecular mechanisms responsible for regulating enrichment of KCNQ channels at the neuronal axon remain elusive. Here, we show that enrichment of KCNQ channels at the axonal surface of dissociated rat hippocampal cultured neurons is regulated by ubiquitous calcium sensor calmodulin. Using immunocytochemistry and the cluster of differentiation 4 (CD4) membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum. Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2/KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon. Consistently, hippocampal neuronal excitability is dampened by transient expression of wild-type KCNQ2 but not mutant KCNQ2 deficient in calmodulin binding. Furthermore, coexpression of mutant calmodulin, which can interact with KCNQ2/KCNQ3 channels but not calcium, reduces but does not abolish their enrichment at the axonal surface, suggesting that apo calmodulin but not calcium-bound calmodulin is necessary for their preferential targeting to the axonal surface. These findings collectively reveal calmodulin as a critical player that modulates trafficking and enrichment of KCNQ channels at the neuronal axon.
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