1.A.1 The Voltage-gated Ion Channel (VIC) Superfamily

Proteins of the VIC family are ion-selective channel proteins found in a wide range of bacteria, archaea, eukaryotes and viruses. They are often homo- or heterooligomeric structures with several dissimilar subunits (e.g., α1-α2-δ-β Ca²⁺ channels, αβ₁β₂ Na⁺ channels or (α)₄-β K⁺ channels), but the channel and the primary receptor is usually associated with the α (or α1) subunit. Functionally characterized members are specific for K⁺, Na⁺ or Ca²⁺. The K⁺ channels usually consist of homotetrameric structures with each α-subunit possessing six transmembrane spanners (TMSs). Many voltage-sensitive K⁺ channels function with β-subunits that modify K⁺ channel gating. These nonintegral β-subunits are oxidoreductases that coassemble with the tetrameric α-subunits in the endoplasmic reticulum and remain tightly adherent to the α-subunit tetramer. The high resolution β-subunit structure is available (Gulbis et al., 1999). Non-homologous β-subunits of Na⁺ and Ca²⁺ channels function in regulation (Hanlon and Wallace, 2002).

The α1 and α subunits of the Ca²⁺ and Na⁺ channels, respectively, are about four times as large as the K⁺ channel α-subunits and possess 4 units, each with 6 TMSs separated by a hydrophilic loop, for a total of 24 TMSs. These large channel proteins form heterotetrameric-unit structures equivalent to the homotetrameric structures of most K⁺ channels. All four units of the Ca²⁺ and Na⁺ channels are homologous to the single unit in the homotetrameric K⁺ channels. Ion flux via the eukaryotic channels is generally controlled by the transmembrane electrical potential (hence the designation, voltage-sensitive) although some are controlled by ligand or receptor binding.

Several putative K⁺-selective channel proteins of the VIC family have been identified in prokaryotes. The structures of two of them, the 2 TMS voltage-insensitive KcsA K⁺ channel of Streptomyces lividans and the 6 TMS KvAP voltage-sensitive K⁺ channel of Aeropyrum pernix, have been solved to 3.2 Å resolution (TC #1.A.1.1.1 and 1.A.1.17.1, respectively) (Doyle et al., 1998; Jiang et al., 2003a,b; Ruta et al., 2003). Both proteins possess four identical subunits, each with two transmembrane helices, arranged in the shape of an inverted teepee or cone, forming the channel. The cone cradles the 'selectivity filter' P domain in its outer end. The narrow selectivity filter is only 12 Å long, whereas the remainder of the channel is wider and lined with hydrophobic residues. A large water-filled cavity and helix dipoles stabilize K⁺ in the pore. The selectivity filter has two bound K⁺ ions about 7.5 Å apart from each other. Ion conduction is proposed to result from a balance of electrostatic attractive and repulsive forces. Evolutionary relationships between K⁺ channels and certain K⁺:cation symporters has been reviewed and discussed (Durell et al., 1999).

The archaeal voltage-dependent K⁺ channel (TC #1.A.1.17.1) has been characterized (Ruta et al., 2003). It exhibits the properties of a classical neuronal K⁺ channel including structural conservation in the voltage sensor as revealed by specific high affinity tarantula venom toxin binding. This toxin evolved to inhibit animal Kv channels.

Three other bacterial VIC family channels have been characterized functionally. One is the 2 TMS LctB channel of Bacillus stearothermophilus (TC #1.A.1.1.2; Wolters et al., 1999), the second is the 6 TMS Kch channel of E. coli (TC #1.A.1.13.1; Ungar et al., 2001), and the third is the Bacillus halodurans 6 TMS voltage-gated Na⁺ channel (TC #1.A.1.14.1; Ren et al., 2001). This last-mentioned protein, called NaChBac, is most similar in sequence to voltage-gated Ca²⁺ channels (TC #1.A.1.11.1-3). A family of these 6 TMS voltage-gated Na⁺ channels (22-54% identical) is widespread in bacteria, suggesting a fundamental function (Koishi et al., 2004). These three proteins are all distantly related to KcsA of S. lividans, particularly LctB. Kch has been shown to form tetramers that may function to maintain the membrane potential in the early stationary phase of growth (Ungar et al., 2001).

In eukaryotes, each VIC family channel type has several subtypes based on pharmacological and electrophysiological data. Thus, there are six types of Ca²⁺ channels (L, N, P, Q, R and T). There are at least ten types of K⁺ channels, each responding in different ways to different stimuli: voltage-sensitive [Ka, Kv, Kvr, Kvs and Ksr], Ca²⁺-sensitive [BK_Ca, IK_Ca and SK_Ca] and receptor-coupled [K_M and K_ACh⁺ channels (I, II, III, μ1, H1 and PN3). Tetrameric channels from both prokaryotic and eukaryotic organisms are known in which each α-subunit possesses 2 TMSs rather than 6, and these two TMSs are homologous to TMSs 5 and 6 of the 6 TMS unit found in the voltage-sensitive channel proteins. KcsA of S. lividans is an example of such a 2 TMS channel protein. These channels may include the K_Na (Na⁺-activated) and K_Vol (cell volume-sensitive) K⁺ channels, as well as distantly related channels such as the Tok1 K⁺ channel of yeast. The TWIK-1 and -2, TREK-1, TRAAK, and TASK-1 and -2 K⁺ channels all exhibit a duplicated 2 TMS unit and may therefore form a homodimeric channel. About 50 of these 4 TMS proteins are encoded in the C. elegans genome. Because of insufficient sequence similarity with proteins of the VIC family, inward rectifier K⁺ IRK channels (ATP-regulated; G-protein-activated) which possess a P domain and two flanking TMSs are placed in a distinct family (TC #1.A.2). However, substantial sequence similarity in the P region suggests that they are homologous. The β, γ and δ subunits of VIC family members, when present, frequently play regulatory roles in channel activation/deactivation.

The generalized transport reaction catalyzed by members of the VIC family is:

cation (out) cation (in).

1.A.1.1.1 - 1BL8
1.A.1.1.1 - 1K4C
1.A.1.1.1 - 1K4D

References:

Examples: