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  • Review Article
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High-conductance potassium channels of the SLO family

Key Points

  • Identification of the Slo gene family came hot on the heels of new advances in molecular cloning, and involved Drosophila melanogaster neurogenetics as well as numerous physiological and biophysical studies. These biophysical studies had identified Ca2+-dependent K+ currents in many systems, as well as unusually large (maxi-K) Ca2+- and Na+-dependent single-channel currents. The key to identifying the genes underlying these phenomena turned out to be the D rosophila slowpoke (slo) mutant.

  • The structures of the α-subunits of SLO family channels resemble those of voltage-gated K+ channels. However, they differ from those of voltage-gated ion channels in that they have an extensive carboxyl extension — the 'tail' — which is thought to confer distinctive properties, such as calcium-sensing, to SLO1 channels, whereas the 'core' domain containing the membrane-spanning segments confers voltage sensitivity.

  • Voltage-dependent channels are gated (opened and closed) in response to changes in transmembrane voltage. In ligand-gated channels, the binding of a ligand, such as a neurotransmitter, causes a conformational change of a 'ligand-binding domain' that is physically coupled to the pore of the channel. For SLO1 and SLO3 channels, this distinction breaks down because both voltage-gating and ligand-gating domains are present, indicating two independent sensing mechanisms that converge near the gates of the pore.

  • A complicated system of cooperativity, involving several Ca2+-sensing sites both on the same subunit and on different subunits, could underlie the responsiveness of SLO1 channels to a broad range of Ca2+ concentrations. This provides versatility and allows these channels to serve a wide variety of physiological roles in different cell types and cellular microdomains, where Ca2+ concentrations can vary extensively.

  • SLO1 channels have the largest single-channel conductance of all K+- selective channels. Several studies have indicated the presence of at least two salient underlying structural mechanisms: two rings of negative charges in the inner and outer pore of the channel's ionic conduction pathway and the size of the SLO1 inner pore region.

  • The functional diversity of SLO1 channels comes from many sources, such as alternative RNA splicing, post-translational modifications and β-subunits. β-subunits alone account for a great deal of diversity, such as enhanced sensitivity to Ca2+ and rapid channel inactivation.

  • The sensitivity of SLO1 to Ca2+ makes it an important negative feedback system for Ca2+ entry in many cell types. SLO1 channels are ubiquitously expressed in most tissues and have roles in neurons, smooth muscles, secretory endocrine cells and specialized sensory receptors.

Abstract

High-conductance, 'big' potassium (BK) channels encoded by the Slo gene family are among the largest and most complex of the extended family of potassium channels. The family of SLO channels apparently evolved from voltage-dependent potassium channels, but acquired a large conserved carboxyl extension, which allows channel gating to be altered in response to the direct sensing of several different intracellular ions, and by other second-messenger systems, such as those activated following neurotransmitter binding to G-protein-coupled receptors (GPCRs). This versatility has been exploited to serve many cellular roles, both within and outside the nervous system.

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Figure 1: Schematic representation of SLO α-subunits.
Figure 2: Properties of SLO1, SLO2 and SLO3 currents.
Figure 3: The S4 region aligned for SLO1, SLO3 and SLO2.
Figure 4: Inter-relatedness of SLO family proteins and similarity to two voltage-dependent channels.

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Acknowledgements

Supported by grants from the National Institutes of Health to L.S.

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Glossary

Delayed rectifier voltage gated K+ channels

Slowly activating and either non-inactivating or very slowly inactivating voltage-sensitive K+-selective channels.

Low-stringency DNA hybridization

A technique in which a radioactively labelled strand of DNA is used to isolate a similar but non-identical strand of DNA.

Inward rectification

A functional property that is characteristic of some ion channels, preferentially permitting an ion current to flow into, rather than out of, a cell.

Afterhyperpolarization

The negative voltage that persists for a short period of time immediately following some action potentials.

M current

A K+ current that is modulated by the activation of muscarinic receptors. It participates in determining the subthreshold excitability of neurons and their responsiveness to synaptic input. The underlying channel is thought to consist of KCNQ K+ channel subunits.

Site-directed mutagenesis

The generation of a mutation at a predetermined position in a DNA sequence by various genetic engineering methods.

Cellular microdomains

Subcellular areas or compartments that have distinctive structural features, such as a clustering of protein complexes.

Symmetrical KCl

Equimolar concentration of KCl on both sides of the membrane.

Selectivity filter

Molecular features in the pore of an ion channel that aid in discriminating between different ion types.

Splice variants

Alternative forms of a protein derived from alternative processing of its mRNA.

Quantal content

The number of quanta — unitary packets of transmitter — released per action potential.

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Salkoff, L., Butler, A., Ferreira, G. et al. High-conductance potassium channels of the SLO family. Nat Rev Neurosci 7, 921–931 (2006). https://doi.org/10.1038/nrn1992

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