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Potassium leak channels and the KCNK family of two-p-domain subunits

Nature Reviews Neuroscience volume 2, pages 175–184 (2001)Cite this article

Abstract

With a bang, a new family of potassium channels has exploded into view. Although KCNK channels were discovered only five years ago, they already outnumber other channel types. KCNK channels are easy to identify because of their unique structure — they possess two pore-forming domains in each subunit. The new channels function in a most remarkable fashion: they are highly regulated, potassium-selective leak channels. Although leak currents are fundamental to the function of nerves and muscles, the molecular basis for this type of conductance had been a mystery. Here we review the discovery of KCNK channels, what has been learned about them and what lies ahead. Even though two-P-domain channels are widespread and essential, they were hidden from sight in plain view — our most basic questions remain to be answered.

Key Points

  • 50 years after leak currents were first described, potassium-selective leak channels have been found —the KCNK channel family. KCNK channels are numerous and widespread. The genes encode unique channel subunits with two pore-forming P domains.

  • Whereas fungi and plants contain variants that operate as non-voltage dependent outward rectifiers, animals have at least 50 genes for the KCNK channels that function as open rectifiers by primarily passing outward current under physiological potassium concentrations.

  • Studies of single KCNK channels have confirmed that leak currents result from channels open at rest and have shown that leak channels are not always open. Instead, like their native counterparts, KCNK channels are subject to strict regulation by second messenger systems.

  • KCNK channels seem to control the excitability of nerves and heart, and perhaps to mediate the effects of volatile anaesthetics. So, neurotransmitter-mediated inhibition of resting potassium flux has an excitatory influence, whereas increased activity with anaesthetic exposure stabilizes cells at rest.

  • Regulation of one KCNK isolate has been observed to reversibly produce leak or voltage-dependent function, modes that stabilize cells and facilitate repetitive excitation, respectively. This significantly expands the functional spectrum of KCNK channels.

  • Many questions regarding KCNK channels remain to be answered. Where are their gates and do they resemble the gates of one-P-domain channels? Do two-P-domain channels function as dimers? Do both pore domains contribute directly to pore formation? Do KCNK subunits form heteromers? What roles do KCNK channels play in health and disease?

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Figure 1: Potassium channels: membrane topology and CURRENT–VOLTAGE RELATIONSHIPS.
Figure 2: KCNK0 single channels open and close, show multi-ion attributes and are regulated.
Figure 3: KCNK2: a leak pore that can also operate as a voltage-gated channel.
Figure 4: KCNK3 channels: molecular correlation with native cardiac and neuronal currents.

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Acknowledgements

This work was supported by grants to S.A.N.G. from the National Institutes of Health. We are grateful to our many colleagues who have shared their thoughts during the preparation of this review: D. A. Bayliss (University of Virginia), M. R. Blatt (University of Glasgow), C. G. Chapman (SBPHRD), J. Daut (Universität Marburg), A. T. Grey (University of California, San Francisco), H. R. Horvitz (MIT), D. Kim (Chicago Medical School), A. Mathie (Imperial College of Science, Technology & Medicine, London), I. Perez de la Cruz (MIT), D. J. Pountney (New York University), L. Salkoff (Washington University, St. Louis), E. Talley (University of Virginia), J. White (HUGO) and S. Yost (University of California, San Francisco).

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Authors and Affiliations

  1. Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, 06536, Connecticut, USA

    Steve A. N. Goldstein, Detlef Bockenhauer, Ita O'Kelly & Noam Zilberberg

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  1. Steve A. N. Goldstein
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Related links

Related links

DATABASE LINKS

TOK1

KCNK0

KCNK1

KCNK2

KCNK3

Kcnk3

KCNK4

KCNK5

KCNK6

KCNK7

Kcnk8

KCNK9

KCO1

Glossary

POLYAMINES

Organic compounds that contain two or more amino groups. Putrescine, spermine and spermidine are prime examples.

MACROSCOPIC CURRENTS

The sum of the ionic currents measured simultaneously from a large population of channels.

Q10

The ratio of reaction rates for a 10°C increase in temperature.

SYMMETRIC IONIC CONDITIONS

Conditions in which the concentration of a particular ion is the same on both sides of a membrane.

CURRENT–VOLTAGE RELATIONSHIP

The changes in ionic current as a function of membrane voltage.

ANOMALOUS MOLE-FRACTION BEHAVIOUR

When two or more ions simultaneously reside inside a channel, their movement through the pore is dependent on each other. When channel conductance is measured as a function of the concentration ratio of two different ionic species and the conductance goes through a minimum rather than changing linearly as the ratio changes, then it is said to show anomalous mole-fraction behaviour.

RELATIVE PERMEABILITY SERIES

A given ion channel can allow the passage of related ionic species, although not all with the same ease. Potassium channels can be grouped by their relative permeability for monovalent cations at equilibrium.

CAROTID BODY

A chemoreceptor organ located above the bifurcation of the common carotid artery. It monitors changes in blood O2 and CO2content and pH, thus helping to control respiratory activity.

ANGIOTENSIN II

Vasoconstrictor octapeptide that acts on the zona glomerulosa of the adrenal cortex to increase aldosterone production and, consequently, to stimulate sodium uptake by the kidney.

M CURRENT

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

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Goldstein, S., Bockenhauer, D., O'Kelly, I. et al. Potassium leak channels and the KCNK family of two-p-domain subunits . Nat Rev Neurosci 2, 175–184 (2001). https://doi.org/10.1038/35058574

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