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Molecular and cellular basis of small- and intermediate-conductance, calcium-activated potassium channel function in the brain
Open accessAbstract
Small conductance calcium-activated potassium (SK or K(Ca)2) channels link intracellular calcium transients to membrane potential changes. SK channel subtypes present different pharmacology and distribution in the nervous system. The selective blocker apamin, SK enhancers and mice lacking specific SK channel subunits have revealed multifaceted functions of these channels in neurons, glia and cerebral blood vessels. SK channels regulate neuronal firing by contributing to the afterhyperpolarization following action potentials and mediating I(AHP), and partake in a calcium-mediated feedback loop with NMDA receptors, controlling the threshold for induction of hippocampal long-term potentiation. The function of distinct SK channel subtypes in different neurons often results from their specific coupling to different calcium sources. The prominent role of SK channels in the modulation of excitability and synaptic function of limbic, dopaminergic and cerebellar neurons hints at their possible involvement in neuronal dysfunction, either as part of the causal mechanism or as potential therapeutic targets.
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![Figure 1 Sequence alignment of the human small conductance Ca2+-activated K+ channels hSK1, hSK2 and hSK3. The putative transmembrane spanning regions, S1–S6, are boxed in gray. The pore region (P-Region) is boxed in turquoise. The calmodulin-binding domain (CaMBD) is indicated by black bars. Amino acids corresponding to phosphorylation consensus sequences for the cyclic AMP- and cyclic GMP-dependent kinases (PKA and PKG) are displayed in red, for protein kinase C (PKC) in blue; and for casein kinase 2 (CK2) boxed in orange. Only intracellular phosphorylation consensus sequences have been labeled for PKA, PKG and PKC, while both intra- and extracellular ones have been highlighted for CK2 because of its potential action as an endo- and ectokinase [263]. Phosphorylation consensus sites have been mapped using the Prosite database: for PKA/PKG: PS00004: [RK](2)-x-[ST]; for PKC: PS00005: [ST]-x-[RK]; for CK2: PS00006: [ST]-x(2)-[DE].](/paper-figures/aaef1bf94b5446dc835b65f8b53f9b28/molecular-and-cellular-basis-of-small-and-intermediate-conductance-calcium-figure-1.jpg)
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“Particularly, small-conductance calcium-activated potassium (SK) channels have been reported to control the spontaneous firing regularity both in vivo and in vitro [80, 81].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [80]
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The control of firing pattern in nigral dopamine neurons: burst firing
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The dopamine hypothesis of reward: past and current status
Spanagel, R., & Weiss, F. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01447-2 · Cited by 977
Small-Conductance, Calcium-Activated Potassium Channels from Mammalian Brain
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Mechanism of calcium gating in small-conductance calcium-activated potassium channels
Xia, X.-M., Fakler, B., Rivard, A., Wayman, G. A., Johnson‐Pais, T. L., Keen, J. E., Ishii, T. M., Hirschberg, B., Bond, C. T., Lutsenko, S., et al. (1998) · Nature · doi:10.1038/26758 · Cited by 866
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Finnie, P. S. B., & Nader, K. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.03.008 · Cited by 189
Fang, X., Jiang, S., Wang, J., Bai, Y., Kim, C. S., Blake, D., Weintraub, N. L., Lei, Y., & Lu, X.-Y. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-01004-x · Cited by 95
Regulation of Hippocampal Gamma Oscillations by Modulation of Intrinsic Neuronal Excitability
Klemz, A., Wildner, F., Tütüncü, E., & Gerevich, Z. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.778022 · Cited by 22
Metadata
- Authors
- Pedarzani, P., & Stocker, M.
- Affiliations
- University College London (GB)
- Corresponding author
- Pedarzani, P.
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2008-07-04
- Volume
- 65
- Issue
- 20
- Pages
- 3196-3217
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC2798969
- OpenAlex
- W2033849297
- Cited by
- 173
- References
- 266
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 11 · 2021: 5 · 2020: 11 · 2019: 10 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 3 · 2014: 14 · 2013: 12 · 2012: 22
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cellular and Molecular Life Sciences (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- small conductance calcium-activated potassium channels, intermediate-conductance calcium-activated potassium channel, apamin, afterhyperpolarization, hippocampal long-term potentiation, neuronal excitability, calcium signaling, glia, cerebral vasculature, synaptic function, dopaminergic neurons, cerebellar neurons, neuronal dysfunction, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Mental Disorders, Brain, Humans, Molecular Sequence Data, Neurons, Small-Conductance Calcium-Activated Potassium Channels, Intermediate-Conductance Calcium-Activated Potassium Channels
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