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.

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Fig. 1.

Phylogenetic tree for the K_v1–9 families. Amino acid sequence alignments of the human channel K_v proteins were created using CLUSTALW, and analysis by maximum parsimony using PAUP^* resulted in unrooted trees comprising the K_v1-K_v6 and K_v8-K_v9 families that appeared in the previous edition of this compendium. Sequences of K_v7.1–7.5, K_v6.4, and K_v8.2 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.

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 β 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.

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Fig. 2.

Phylogenetic tree for the K_v10–12 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.

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).