An ancestral MAGUK protein supports the modulation of mammalian voltage-gated Ca channels through a conserved Caβ-like interface.

Eukaryote voltage-gated Ca channels of the Ca2 channel family are hetero-oligomers formed by the pore-forming Caα1 protein assembled with auxiliary Caα2δ and Caβ subunits. Caβ subunits are formed by a Src homology 3 (SH3) domain and a guanylate kinase (GK) domain connected through a HOOK domain. The GK domain binds a conserved cytoplasmic region of the pore-forming Caα1 subunit referred as the "AID".

Unique cysteine-enriched, D2L5 and D4L6 extracellular loops in Ca3 T-type channels alter the passage and block of monovalent and divalent ions.

Invertebrate LCa3 shares the quintessential features of vertebrate Ca3 T-type channels, with a low threshold of channel activation, rapid activation and inactivation kinetics and slow deactivation kinetics compared to other known Ca channels, the Ca1 and Ca2 channels. Unlike the vertebrates though, Ca3 T-type channels in non-cnidarian invertebrates possess an alternative exon 12 spanning the D2L5 extracellular loop, which alters the invertebrate LCa3 channel into a higher Na and lower Ca current passing channel, more resembling a classical Na1 Na channel. Cnidarian Ca3 T-type channels can possess genes with alternative cysteine-rich, D4L6 extracellular loops in a manner reminiscent of the alternative cysteine-rich, D2L5 extracellular loops of non-cnidarian invertebrates.

Eukaryotic Voltage-Gated Sodium Channels: On Their Origins, Asymmetries, Losses, Diversification and Adaptations.

The appearance of voltage-gated, sodium-selective channels with rapid gating kinetics was a limiting factor in the evolution of nervous systems. Two rounds of domain duplications generated a common 24 transmembrane segment (4 × 6 TM) template that is shared amongst voltage-gated sodium (Na1 and Na2) and calcium channels (Ca1, Ca2, and Ca3) and leak channel (NALCN) plus homologs from yeast, different single-cell protists (heterokont and unikont) and algae (green and brown). A shared architecture in 4 × 6 TM channels include an asymmetrical arrangement of extended extracellular L5/L6 turrets containing a 4-0-2-2 pattern of cysteines, glycosylated residues, a universally short III-IV cytoplasmic linker and often a recognizable, C-terminal PDZ binding motif.