NALCN Ion Channels Have Alternative Selectivity Filters Resembling Calcium Channels or Sodium Channels
Figure 9
Conservation patterns suggest greater flexibility in calcium and sodium selectivity in 4-domain cation channels before vertebrate evolution.
All 4-domain cation channels first existed with calcium-selective pores (i.e. Cav (EEEE), Nav (DEEA) and NALCN (EEEE)). The first sodium-selective pores (DKEA) arose in extant relatives of the simplest animals with pelagic lifestyles and nervous systems (e.g. hydrozoan jellyfish) that produce sodium-dependent action potentials. Dual sodium- and calcium-selectivity evolved for all 4-domain channel types (excluding Cav1 and Cav2 channels) by different means. Traditional Nav channels, such as the 10 vertebrate Nav genes, have mostly DEKA selectivity filter pores (i.e. Nav1), with closely-related but more calcium-selective Nav2 channel genes with DEEA pores. Dual sodium- and calcium-selectivity also arose for NALCN and T-type channels, via alternative splicing of channel pores. In general, vertebrate ion channels becomes more exclusively sodium- or calcium-selective, with loss of a calcium-selective Nav2 gene, and loss of a NALCN splice isoform with the calcium selectivity filter (EEEE) and loss of T-type calcium channels with a capacity for sodium permeation.