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IUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. LV. Nomenclature and Molecular Relationships of Two-P Potassium Channels

Department of Pediatrics and Institute for Molecular Pediatric Sciences. Pritzker School of Medicine, University of Chicago, Chicago, Illinois (S.A.N.G., L.D.P., S.R.); Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia (D.A.B.); Department of Physiology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, Chicago, Illinois (D.K.); and Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France (F.L.)

Introduction

In less than a decade since their discovery, the study of K_2P channels has revealed that background leak of potassium ions via dedicated pathways is a highly regulated mechanism to control cellular excitability. Potassium leak pathways, active at rest, stabilize membrane potential below firing threshold and expedite repolarization. Although the existence of leak currents was proposed in 1952 by Hodgkin and Huxley, they remained a biophysical curiosity for more than 4 decades. Identification of the first molecular correlate of a potassium leak current was preceded by cloning of potassium channels in Saccharomyces cerevisiae and Caenorhabditis elegans with two pore-forming P loops in each subunit and four or eight transmembrane (TM¹) domains (Ketchum et al., 1995). Thereafter, K_2PØ was isolated by functional expression cloning from the neuromuscular tissue of Drosophilia melanogaster (Goldstein et al., 1996). Biophysical characterization revealed K_2PØ to be a potassium-selective channel with the predicted attributes of a background conductance, that is, a voltage-independent portal showing Goldman-Hodgkin-Katz (open) rectification. When the concentration of potassium is symmetrical across the membrane, K_2PØ currents change in a linear manner with voltage; under physiological conditions (high internal and low external potassium), K_2PØ passes greater outward than inward currents (Goldstein et al., 2001).

A striking feature of K_2P channels is their subunit body plan: each has two P loops and four TM domains. This distinct 2P/4TM topology can be found in more than 70 predicted homologs in genome databases. Fifteen mammalian genes in the family are designated as KCNK genes encoding the K_2P channels (Fig. 1); most readily reveal ion channel function upon expression. As expected for regulators of excitability, K_2P channels are under tight control by a plethora of chemical and physical stimuli, including oxygen tension, pH, lipids, mechanical stretch, neurotransmitters, and G protein-coupled receptors; the channels are also the molecular targets for certain volatile and local anesthetics (Lesage and Lazdunski, 2000). Regulation of K_2P channels alters the attributes subject to change in any ion channel: number of pores at the site of operation, open probability, and unitary current (Plant et al., 2005). Nonetheless, some regulatory changes are striking; for example, phosphorylation of K_2P2 endows the open rectifier with sensitivity to voltage (Bockenhauer et al., 2001), and desumoylation of K_2P1 (removal of covalently-bound small ubiquitin-modifier protein) relieves chronic silencing of complexes that reside in the plasma membrane, thereby revealing that the protein can function as an ion channel and operates like K_2PØ as an open rectifier (Plant et al., 2005; Rajan et al., 2005). Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 present the properties of K_2P1.1 through K_2P18.1 channels.

View larger version (26K): [in this window] [in a new window]   FIG. 1. Phylogenetic tree for K2P channels. Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human K2P family were generated as described in the legend for Fig. 1 of "LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels." K2P18.1 was added to the topology shown in the previous edition of this compendium by use of maximum parsimony and neighbor-joining algorithms. International Union of Pharmacology and HUGO Gene Nomenclature Committee names of the genes are shown together with their chromosomal localization.

Address correspondence to: Dr. Steve A. N. Goldstein, Department of Pediatrics and Institute for Molecular Pediatric Sciences, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637. E-mail: sangoldstein{at}uchicago.edu

Footnotes

Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.57.4.12.

¹ Abbreviations: TM, transmembrane.

References

Bockenhauer D, Zilberberg N, and Goldstein SA (2001) KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci 4: 486-491.[Medline]

Goldstein SA, Bockenhauer D, O'Kelly I, and Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2: 75-84.[CrossRef]

Goldstein SAN, Price LA, Rosenthal DN, and Pausch MH (1996) ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93: 13256-13261.[Abstract/Free Full Text]

Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, and Goldstein SAN (1995) A new family of outwardly-rectifying potassium channel proteins with two pore domains in tandem. Nature (Lond) 376: 690-695.[CrossRef][Medline]

Lesage F and Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Renal Physiol. 279: F793-F801.[Abstract/Free Full Text]

Plant LD, Rajan S, and Goldstein SA (2005) K2P channels and their protein partners. Curr Opin Neurobiol 15: 326-333.[CrossRef][Medline]

Rajan S, Plant LD, Rabin ML, Butler MH, and Goldstein SAN (2005) Sumoylation silences the plasma membrane leak K⁺ channel K2P1. Cell 121: 37-47.[CrossRef][Medline]

All authors serve as the Subcommittee on K_2P Channels of the Nomenclature Committee of the International Union of Pharmacology.

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