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Invertebrate LCa V 3 shares the quintessential features of vertebrate Ca V 3 T-type channels, with a low threshold of channel activation, rapid activation and inactivation kinetics and slow deactivation kinetics compared to other known Ca 2+  channels, the Ca V 1 and Ca V 2 channels. Unlike the vertebrates though, Ca V 3 T-type channels in non-cnidarian invertebrates possess an alternative exon 12 spanning the D2L5 extracellular loop, which alters the invertebrate LCa V 3 channel into a higher Na +  and lower Ca 2+  current passing channel, more resembling a classical Na V 1 Na +  channel. Cnidarian Ca V 3 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. We illustrate here that the preferences for greater Na +  or Ca 2+  ion current passing through Ca V 3 T-type channels are contributed by paired cysteines within D2L5 and D4L6 extracellular loops looming above the pore selectivity filter. Swapping of invertebrate tri- and tetra-cysteine containing extracellular loops, generates higher Na +  current passing channels in human Ca V 3.2 channels, while corresponding mono- and di-cysteine loop pairs in human Ca V 3.2 generates greater Ca 2+  current passing, invertebrate LCa V 3 channels. Alanine substitutions of unique D2L5 loop cysteines of LCa V 3 channels increases relative monovalent ion current sizes and increases the potency of Zn 2+  and Ni 2+  block by ~ 50× and ~ 10× in loop cysteine mutated channels respectively, acquiring characteristics of the high affinity block of Ca V 3.2 channels, including the loss of the slowing of inactivation kinetics during Zn 2+  block. Charge neutralization of a ubiquitous aspartate residue of calcium passing Ca V 1, Ca V 2 and Ca V 3 channels, in the outer pore of the selectivity filter residues in Domain II generates higher Na +  current passing channels in a manner that may resemble how the unique D2L5 extracellular loops of invertebrate Ca V 3 channels may confer a relatively higher peak current size for Na +  ions over Ca 2+  The extracellular loops of Ca V 3 channels are not engaged with accessory subunit binding, as the other Na +  (Na V 1) and Ca 2+  (Ca V 1/Ca V 2) channels, enabling diversity and expansion of cysteine-bonded extracellular loops, which appears to serve, amongst other possibilities, to alter to the preferences for passage of Ca 2+  or Na +  ions through invertebrate Ca V 3 channels.

Unique cysteine-enriched, D2L5 and D4L6 extracellular loops in CaV3 T-type channels alter the passage and block of monovalent and divalent ions