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IUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels

Department of Microbiology and Molecular Genetics (G.A.G.) and Physiology and Biophysics (K.G.C.), University of California, Irvine, Irvine, California; Department of Applied Physiology, Universitat Ulm, Ulm, Germany (S.G.); Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Valbonne, France (M.L.); Department of Neurobiology and Behavior, The State University of New York at Stony Brook, Health Sciences Center, Stony Brook, New York (D.M.); Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin (G.A.R.); Department of Physiology, Neuroscience, and Biochemistry, New York University School of Medicine, New York, New York (B.R.); Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah (M.C.S.); Max Planck Institute for Experimental Medicine, Abt. Molekulare Biologie Neuronaler Signale, Gottingen, Germany (L.A.P., W.S.); and Institute of Materia Medica, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China (X.W.)

Introduction

Potassium-selective channels are the largest and most diverse group of ion channels, represented by some 70 known loci in the mammalian genome. The first cloned potassium channel gene was the Drosophila voltage-gated shaker channel, and this was rapidly followed by the identification of other voltage- and ligand-gated potassium channel genes in flies, mammals, and many other organisms. The voltage-gated K_v channels, in turn, form the largest family of some 40 genes among the group of human potassium channels, which also includes the Ca²⁺-activated (K_Ca), inward-rectifying (K_IR), and two-pore (K_2P) families described in the following articles of this compendium. K_v and K_Ca channels together constitute the six/seven-transmembrane group of potassium-selective channels, made up of subunits containing six or seven membrane-spanning domains, including the positively charged S4 segment, which confers on some of these channels their voltage sensitivity.

Table 1 lists the International Union of Pharmacology (IUPHAR¹) names assigned to the members of the K_v family of channels, as well as the gene names established by the HUGO Gene Nomenclature Committee (HGNC). Two new sequences, K_v6.4 and K_v8.2, have been added to this list since the earlier edition of this compendium. Figures 1 and 2 show two phylogenetic tree reconstructions, one for the K_v1–9 families and the other for the K_v10–12 families, based on amino acid sequence alignments of the entire hydrophobic core of the proteins.

View this table: [in this window] [in a new window]   TABLE 1 KV channel families Gene names shown are those assigned by the IUPHAR (Catterall et al., 2002) and HGNC (http://www.gene.ucl.ac.uk) in addition to some other commonly used names.

View larger version (28K): [in this window] [in a new window]   FIG. 1. Phylogenetic tree for the Kv1–9 families. Amino acid sequence alignments of the human channel Kv proteins were created using CLUSTALW, and analysis by maximum parsimony using PAUP* resulted in unrooted trees comprising the Kv1-Kv6 and Kv8-Kv9 families that appeared in the previous edition of this compendium. Sequences of Kv7.1–7.5, Kv6.4, and Kv8.2 were added to the existing alignment, and these new sequences were incorporated into the existing tree topology by use of a combination of maximum parsimony and neighbor-joining analysis. Only the hydrophobic cores (S1–S6) were used for analysis. The IUPHAR and HGNC names are shown together with the genes' chromosomal localization and other commonly used names.

View larger version (22K): [in this window] [in a new window]   FIG. 2. Phylogenetic tree for the Kv10–12 families. This unrooted tree was created as described in Fig. 1 and appeared in the previous edition of this compendium. The IUPHAR and HGNC names are shown together with the genes' chromosomal localization and other commonly used names.

K_v channels form an exceedingly diverse group, much more so than one would predict simply based on the number of distinct genes that encode them. This diversity arises from several factors. 1) Heteromultimerization. Each K_v gene encodes a peptide subunit, four of which are required to form a functional channel. K_v channels may be homotetramers but may also be heterotetramers formed between different subunits within the same family (in the case of the K_v1, K_v7, and K_v10 families), and these diverse heterotetramers express properties that may be considerably different from those of any of the homotetramers. 2) "Modifier" subunits. Four of the K_v families (K_v5, 6, 8, and 9) encode subunits that act as modifiers. Although these do not produce functional channels on their own, they form heterotetramers with K_v2 family subunits, increasing the functional diversity within this family. 3) Accessory proteins. A variety of other peptides has also been shown to associate with K_v tetramers and modify their properties, including several subunits (which associate with K_v1 and K_v2 channels), KCHIP1 (K_v4), calmodulin (K_v10), and minK (K_v11), as well as many others identified in the tables that follow the text of this article. 4) Alternate mRNA splicing. A number of K_v channel genes are known to contain intronless coding regions, including all of the K_v1 family genes (with the sole exception of K_v1.7) and K_v9.3. Although alternate splicing of noncoding exons may be important in regulating the expression of these channels, one gene can produce only a single kind of protein subunit. However, various members of the K_v3, 4, 6, 7, 9, 10, and 11 gene families have coding regions made up of several exons that are alternately spliced, providing yet another significant source of K_v channel functional diversity. 5) Post-translational modification. Many K_v channels can be post-translationally modified by phosphorylation (Jerng et al., 2004), ubiquitinylation (Henke et al., 2004), and palmitoylation (Gubitosi-Klug et al., 2005), which in turn modifies channel function.

Our current understanding of the roles of this family of channels is catalogued in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, including recent developments in the pharmacology, regulation of expression, and disease associations of its various members (Misonou and Trimmer, 2004; Norton et al., 2004; Wua and Dworetzky, 2005).

Address correspondence to: Dr. George A. Gutman, Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA. E-mail: gagutman{at}uci.edu

Footnotes

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

doi:10.1124/pr.57.4.10.

¹ Abbreviations: IUPHAR, International Union of Pharmacology; HGNC, HUGO Gene Nomenclature Committee.

References

Catterall WA, Chandy KG, and Gutman GA, eds. (2002) The IUPHAR Compendium of Voltage-gated Ion Channels. IUPHAR Media, Leeds, UK.

Gubitosi-Klug RA, Mancuso DJ, and Gross RW (2005) The human Kv1.1 channel is palmitoylated, modulating voltage sensing: identification of a palmitoylation consensus sequence. Proc Natl Acad USA 102: 5964-5968.[Abstract/Free Full Text]

Henke G, Maier G, Wallisch S, Boehmer C, and Lang F (2004) Regulation of the voltage gated K⁺ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol 199: 194-199.[CrossRef][Medline]

Jerng HH, Pfaffinger PJ, and Covarrubias M (2004) Molecular physiology and modulation of somatodendriticA-type potassium channels. Mol Cell Neurosci 27: 343-369.[CrossRef][Medline]

Misonou H and Trimmer JS (2004) Determinants of voltage-gated potassium channel surface expression and localization in mammalian neurons. Crit Rev Biochem Mol Biol 39: 125-145.[CrossRef][Medline]

Norton RS, Pennington MW, and Wulff H (2004) Potassium channel blockade by the sea anemone toxin ShK for the treatment of multiple sclerosis and other autoimmune diseases. Curr Med Chem 11: 3041-3052.[Medline]

Wua YJ and Dworetzky SI (2005) Recent developments on KCNQ potassium channel openers. Curr Med Chem 12: 453-456.[Medline]

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