FIG. 1. Representation of the amino acid relationships of the minimal pore regions of the voltage-gated ion channel superfamily. This global view of the 143 members of the structurally related ion channel genes highlights seven groups of ion channel families and their membrane topologies. Four-domain channels (CaV and NaV) are shown as blue branches, potassium-selective channels are shown as red branches, cyclic nucleotide-gated channels are shown as magenta branches, and TRP and related channels are shown as green branches. Background colors separate the ion channel proteins into related groups: light blue, CaV and NaV; light green, TRP channels; light red, potassium channels, except KV10–12, which have a cyclic nucleotide binding domain and are more closely related to CNG and HCN channels; light orange, KV10–12 channels and cyclic nucleotide-modulated CNG and HCN channels. Minimal pore regions bounded by the transmembrane segments M1/S5 and M2/S6 were aligned by ClustalX (Thompson et al., 1997) and refined manually. The pore regions of the fourth homologous domain of NaV and CaV channels, the second domain of the two-pore channels (TPC), and the first pore regions of the K2P channels were used to assemble the alignment, and an unrooted consensus tree was built by minimum evolution analysis using PAUP version 4.0b10 software (Swofford, 2003). To confirm the significance of the relationship among the families that comprise the VGL ion channel superfamily, we tested the significance of the amino acid sequence relationships using the HMM searching procedure. HMM searches of the complete RefSeq database revealed that each ion channel family profile identified another family of voltage-gated-like ion channels as the nearest relative in amino acid sequence of its pore. For example, for the KV channel profile, the nearest neighbor was CNGA1 (HMM e-value of 2.6 103); for the cyclic nucleotide-modulated channel profile, KV11.2 (HMM e-value of 1.5 106); for the TRP channel profile, CaV3.1 (HMM e-value of 1.8 103); and for the NaV/CaV profile, CatSper (HMM e-value of 9.4 106). The e-value is a measure of the number of hits from HMM searches that would be expected by chance; values less than 1.0 indicate a highly significant amino acid sequence relationship to the probe profile (Yu and Catterall, 2004).
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