Introduction

The second major group of six/seven transmembrane potassium-selective channels consists of the K_Ca channels (for reviews, see Lingle, 2002; Magleby, 2003; Moczydlowski, 2004; Stocker, 2004; Cox, 2005), and Table 1 shows the International Union of Pharmacology (IUPHAR¹) names of the members of this group together with their HUGO Gene Nomenclature Committee (HGNC) designations and other commonly used names. The phylogenetic trees in Fig. 1 illustrate the fact that these channels form two well defined but only distantly related groups.

One of these groups (Fig. 1A) includes the three “small-conductance” K_Ca channels (K_Ca2.1, 2.2, and 2.3) (Kohler et al., 1996) and the “intermediate-conductance” channel K_Ca3.1 (Ishii et al., 1997; Joiner et al., 1997). These channels are voltage-insensitive and are activated by low concentrations of internal Ca²⁺ (<1.0 μM), in contrast to K_Ca1.1 (KCNMA1, Slo1), which is activated by both voltage and internal Ca²⁺. The three small-conductance K_Ca channels are sensitive to block by apamin (100 pM–10 nM), which distinguishes them from all other K_Ca channels. Both small- and intermediate-conductance K_Ca channels play important roles in many processes involving Ca²⁺-dependent signaling in both electrically excitable and nonexcitable cells. They do not bind Ca²⁺ directly but rather detect Ca²⁺ by virtue of calmodulin, which is constitutively bound to the C-terminal region (Xia et al., 1998; Fanger et al., 1999). Binding of calcium to this calmodulin results in conformational changes that are in turn responsible for channel gating (Schumacher et al., 2001).

The tree shown in Fig. 1B illustrates the sequence relationships within the second group of K_Ca channels, which includes K_Ca1.1 (Slo or Slo1), K_Ca4.1 (Slack or Slo2.2), K_Ca4.2 (Slick or Slo2.1), and K_Ca5.1 (Slo3). K_Ca1.1 has been extensively studied in the brain, cochlea, and muscle, and alternate splicing of its mRNA is known to produce considerable functional diversity (Weiger et al., 2002; Faber and Sah, 2003). Unlike the K_Ca2 and K_Ca3 channels, binding of calcium by K_Ca1.1 is not dependent on its association with calmodulin but is thought to be mediated by at least three divalent cation binding sites in the cytoplasmic carboxyl domain of each channel subunit. Two independent high-affinity Ca²⁺ binding sites are formed by a negatively charged segment in the distal carboxyl terminal portion, termed the “calcium bowl” (Schreiber and Salkoff, 1997) and within the first RCK domain encoded by the proximal C-terminal portion (Bao et al., 2002; Xia et al., 2002). A third low-affinity divalent cation binding site is also found in the first RCK domain (Shi et al., 2002), which contributes to activation by Mg²⁺ and Ca²⁺ at high concentrations (>1 mM).

The three other members of this group, K_Ca4.1, 4.2, and 5.2 (Joiner et al., 1997; Schreiber et al., 1998; Yuan et al., 2003), were all included in the K_Ca nomenclature since they all are clearly members of this structurally related group of genes. However, much more is now known about the functional properties of the members of this gene family than was known when these names were assigned several years ago, and this presents a possible conundrum for a nomenclature based on functional rather than structural similarity. Unlike the founding member K_Ca1.1, which is in fact activated by internal Ca²⁺, none of the other members of this group seems to be similarly Ca²⁺-activated. In fact, for the most part, these three are insensitive to internal Ca²⁺. K_Ca4.2 and K_Ca4.1 are activated by internal Na⁺ and Cl^- (Yuan et al., 2003), and K_Ca5.1 is activated by internal alkalization (OH^-) (Schreiber et al., 1998). Therefore, although they are structurally related to K_Ca1.1, these three channels cannot correctly be described as “calcium-activated” channels based on functional criteria. This may be a subject for discussion among researchers in this field and those bodies responsible for standardizing gene nomenclature.

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Fig. 1.

Phylogenetic tree for K_Ca channels. A, K_Ca2/3 group. B, K_Ca1/4/5 group. Amino acid sequence alignments and phylogenetic analysis for these two groups of four human K_Ca channels were generated as described in the legend for Fig. 1 of “International of Union of Pharmacology LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels.” No new channels have been added to these topologies since they appeared in the earlier edition of this compendium. IUPHAR and HGNC names of the genes are shown together with other commonly used names and their chromosomal localization.

Tables 2, 3, 4, 5, 6, 7, 8, 9 present the K_Ca1.1 through K_Ca 5.1 channels.