Gene Splicing of an Invertebrate Beta Subunit (LCav beta ) in the N-Terminal and HOOK Domains and Its Regulation of LCav1 and LCav2 Calcium Channels: e92941

The accessory beta subunit (Cav beta ) of calcium channels first appear in the same genome as Cav1 L-type calcium channels in single-celled coanoflagellates. The complexity of this relationship expanded in vertebrates to include four different possible Cav beta subunits ( beta 1, beta 2, beta 3, beta 4) which associate with four Cav1 channel isoforms (Cav1.1 to Cav1.4) and three Cav2 channel isoforms (Cav2.1 to Cav2.3). Here we assess the fundamentally-shared features of the Cav beta subunit in an invertebrate model (pond snail Lymnaea stagnalis) that bears only three homologous genes: (LCav1, LCav2, and LCav beta ). Invertebrate Cav beta subunits (in flatworms, snails, squid and honeybees) slow the inactivation kinetics of Cav2 channels, and they do so with variable N-termini and lacking the canonical palmitoylation residues of the vertebrate beta 2a subunit. Alternative splicing of exon 7 of the HOOK domain is a primary determinant of a slow inactivation kinetics imparted by the invertebrate LCav beta subunit. LCav beta will also slow the inactivation kinetics of LCav3 T-type channels, but this is likely not physiologically relevant in vivo. Variable N-termini have little influence on the voltage-dependent inactivation kinetics of differing invertebrate Cav beta subunits, but the expression pattern of N-terminal splice isoforms appears to be highly tissue specific. Molluscan LCav beta subunits have an N-terminal "A" isoform (coded by exons: 1a and 1b) that structurally resembles the muscle specific variant of vertebrate beta 1a subunit, and has a broad mRNA expression profile in brain, heart, muscle and glands. A more variable "B" N-terminus (exon 2) in the exon position of mammalian beta 3 and has a more brain-centric mRNA expression pattern. Lastly, we suggest that the facilitation of closed-state inactivation (e.g. observed in Cav2.2 and Cav beta 3 subunit combinations) is a specialization in vertebrates, because neither snail subunit (LCav2 nor LCav beta ) appears to be compatible with this observed property.