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Ca2+-activated K+ channels: molecular determinants and function of the SK family

Nature Reviews Neuroscience volume 5, pages 758–770 (2004)Cite this article

Key Points

  • Ca2+-activated K+ (KCa) channels have evolved to use Ca2+ to regulate their opening and closing (gating), and to support the ability of the cell to finely regulate the amount of Ca2+ that is able to enter. This review describes the molecular and functional properties of KCa channels of small and intermediate conductance (SK and IK channels, respectively).

  • The genes that encode the three SK channels KCa2.1, KCa2.2 and KCa2.3 belong to the KCNN gene family. The closely related family member KCa3.1 was named IK on the basis of its intermediate single-channel conductance. The structures of the SK-channel genes are complex, and there is evidence of alternative splicing.

  • SK channels have a similar topology to members of the voltage-gated (Kv) K+ channel superfamily, which consist of six transmembrane segments with the pore located between segments 5 and 6. The S4 segment, which confers voltage sensitivity to the Kv channel, contains a reduced number of positively charged amino acids in SK channels, which might explain their observed voltage independence.

  • KCa2.1, KCa2.2, and KCa2.3 channels are predominantly expressed in the nervous system, whereas the KCa3.1 channel is mainly expressed in blood and epithelial cells, and in some peripheral neurons. The expression patterns in the brain indicate that specific SK-channel subunits contribute to neuronal excitability and function in different regions, and possibly in different neuronal compartments.

  • Ca2+ sensitivity seems to be conferred on the KCa2.2 channel by the intimate interaction of calmodulin (CaM) with each of the four subunits, and it is generally accepted that CaM has a role in the gating of all KCa2 and KCa3 channels. CaM is also essential for the assembly and trafficking of SK-channel subunits.

  • In central neurons, SK channels mediate an apamin-sensitive K+ current that is known as IAHP, which contributes to the generation of an afterhyperpolarization of medium duration (mAHP) that follows single, or bursts of, action potentials. Depending on the neuronal subtype and its contingent of ion channels, the IAHP might contribute to the instantaneous firing rate, set the tonic firing frequency or regulate burst firing and rhythmic oscillatory activity.

  • SK channels are functionally coupled to Ca2+ sources: apamin-sensitive currents are coupled to the activation of different subtypes of voltage-gated Ca2+ channels in a cell-type-specific manner, and there is also evidence for SK-channel activation by Ca2+ that is released from intracellular stores.

  • The SK-channel blocker apamin has been used in behavioural studies to investigate the role of the SK channels in cognitive functions. SK-channel blockade improves performance on hippocampus-dependent learning tasks, and it seems to facilitate the induction of long-term potentiation in the hippocampal formation by increasing postsynaptic neuronal excitability.

  • Questions that remain to be answered concern the molecular make-up of native SK channels in different brain regions, their localization in specific neuronal compartments and their functional coupling and interplay with Ca2+ sources. A better understanding of SK-channel physiology might also clarify their hypothesized role in various pathological conditions.

Abstract

Ca2+-activated K+ (KCa) channels of small (SK) and intermediate (IK) conductance are present in a wide range of excitable and non-excitable cells. On activation by low concentrations of Ca2+, they open, which results in hyperpolarization of the membrane potential and changes in cellular excitability. KCa-channel activation also counteracts further increases in intracellular Ca2+, thereby regulating the concentration of this ubiquitous intracellular messenger in space and time. KCa channels have various functions, including the regulation of neuronal firing properties, blood flow and cell proliferation. The cloning of SK and IK channels has prompted investigations into their gating, pharmacology and organization into calcium-signalling domains, and has provided a framework that can be used to correlate molecularly identified KCa channels with their native currents.

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Figure 1: Gene structure and single-channel properties of SK channels.
Figure 2: Interaction of SK channels with calmodulin and calcium–calmodulin-dependent gating.
Figure 3: SK-channel expression in the CNS.
Figure 4: Effect of SK-channel enhancers on the excitability of hippocampal neurons.
Figure 5: SK channels, firing patterns and spike-timing precision.
Figure 6: Physical and functional coupling of SK channels to Calcium sources.

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Acknowledgements

I would like to thank my colleagues J. P. Adelman, R. Andrade and K. G. Chandy for sharing their results before publication. I am grateful to A. C. Dolphin and D. A. Brown, and to the members of my group, D. D'hoedt, T. Ferraro, K. Hirzel, D. Kerschensteiner and A. Nolting, for comments on the manuscript. I am indebted to P. Pedarzani for invaluable discussions and constructive criticism on this review. Research in my laboratory is supported by the Wellcome Trust. The author is a Wellcome Trust Senior Research Fellow.

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  1. Department of Pharmacology, Wellcome Laboratory for Molecular Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Martin Stocker

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DATABASES

Entrez Gene

KCa2.1

KCa2.2

KCa2.3

KCa3.1

Molecular Modeling Database

Crystal structure of the CaM-CaMBD in the presence of Ca2+ of the of the Ca2+-activated potassium channel (SK2) (16082)

Solution structure (NMR of the CaMBD of the Ca2+-activated potassium channel (SK2) (18380)

FURTHER INFORMATION

Stocker laboratory homepage

Potassium channel diversity

Potassium channel gene family nomenclature

Calmodulin target database

Glossary

MULTIMERS, HOMOMERS AND HETEROMERS

Channels that are formed by the assembly of two or more subunits (multimers), of the same type (homomers) or of different types (heteromers).

SELECTIVITY

The property of a channel that allows only some ions to pass through its pore; other ions might be able to pass with great difficulty, and others not at all.

AFTERHYPERPOLARIZATION

(AHP) Hyperpolarization of the membrane potential following single or multiple action potentials.

SPIKE-FREQUENCY ADAPTATION

Progressive reduction in the frequency of action-potential firing or, in extreme cases, complete cessation of firing after some initial action potentials in response to constant depolarization above the firing threshold.

PARALOGOUS

Paralogous genes are genes that occur within the same species that have arisen from a common ancestor by duplication and subsequent divergence. For example, the mouse α-globin and β-globin genes are paralogues.

ORTHOLOGOUS

Genes in different species are orthologues if they have evolved from a single common ancestral gene. For example, the β-globin genes of mouse, rat and human are orthologues. Note that several genes in the mouse or rat might have a single orthologue in another species, and vice versa.

ALTERNATIVE SPLICING

A post-transcriptional process through which a pre-mRNA molecule, containing several introns and exons, can lead to different functional mRNA molecules, and consequently proteins, that originate from a single gene.

GIANT PATCH

Giant membrane patches are commonly obtained to enable studies of membrane currents of cells that are too large to record with conventional patch-clamp methods.

INWARD RECTIFICATION

A phenomenon that describes the diode-like behaviour of a channel that shows an increased conductance with hyperpolarization and a decreased conductance with depolarization. The channels are called inward rectifiers because current flows through them more easily into, than out of, the cell.

EF-HAND MOTIF

A common Ca2+-binding motif. It consists of a 12-amino-acid loop with a 12-amino-acid α-helix at either end, providing octahedral coordination for Ca2+.

IQ MOTIF

Proteins that contain IQ motifs typically bind CaM in the absence of Ca2+, although there are some exceptions. The IQ motif has the sequence (F/I/L/V)QXXX(R/K)GXXX(R/K)XX(F/I/L/V/W/Y). Characters within parentheses can substitute for each other, and X can be any amino acid.

1:8:14 AND 1:5:8:14 MOTIF

Subclasses of the 1:14 motif, where two hydrophobic residues are spaced 12 amino acids apart, with additional anchoring residues in the middle. These terms refer to sequences that mediate Ca2+-dependent calmodulin binding. The 1:8:14 motif has the sequence (F/I/L/V/W)XXXXXX(F/A/I/L/V/W)XXXXX(F/I/L/V/W), and the 1:5:8:14 motif has the sequence (F/I/L/V/W/)XXX(F/A/I/L/V/W)XX(F/A/I/L/V/W)XXXXX(F/I/L/V/W). Characters within parentheses can substitute for each other, and X can be any amino acid.

CYSTEINE-ACCESSIBILITY MUTAGENESIS

A method that is used to characterize channels and binding sites. Single native amino acids are mutated to cysteine, and the ability of sulphydryl reacting and coordinating reagents to react with the cysteines is then tested.

IC50

The IC50 is commonly defined as the drug concentration at which the response has decreased to 50% of the initial response.

CHIMERIC SUBUNIT/CHANNEL

A subunit that contains sequences that are derived from at least two different genes. In the case of a multimeric channel, the assembly of chimeric subunits then results in the generation of a chimeric channel.

IN SITU HYBRIDIZATION

A method for labelling and localizing mRNA within cells.

RT-PCR

Reverse transcriptase-polymerase chain reaction. This method allows amplification (PCR) of mRNA sequence after synthesis of a complementary DNA molecule by reverse transcriptase (RT).

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Stocker, M. Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci 5, 758–770 (2004). https://doi.org/10.1038/nrn1516

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