Abstract
The accessory beta subunit (Cavβ) 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 Cavβ subunits (β1, β2, β3, β4) 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 Cavβ subunit in an invertebrate model (pond snail Lymnaea stagnalis) that bears only three homologous genes: (LCav1, LCav2, and LCavβ). Invertebrate Cavβ 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 β2a subunit. Alternative splicing of exon 7 of the HOOK domain is a primary determinant of a slow inactivation kinetics imparted by the invertebrate LCavβ subunit. LCavβ 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 Cavβ subunits, but the expression pattern of N-terminal splice isoforms appears to be highly tissue specific. Molluscan LCavβ subunits have an N-terminal “A” isoform (coded by exons: 1a and 1b) that structurally resembles the muscle specific variant of vertebrate β1a 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 β3 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 Cavβ3 subunit combinations) is a specialization in vertebrates, because neither snail subunit (LCav2 nor LCavβ) appears to be compatible with this observed property.
Highlights
Unique ancillary beta subunits are identifiable in the proteosomal complex with different voltage-gated ion channels including K [1,2,3], Na+ [4,5,6] and Ca2+ [7,8,9] channels
All Cav1 and Cav2 channels from simple representatives have a hallmark alpha1-interaction domain (AID) sequence [34] for associating with Cavb subunits, which enables a promiscuity and interchangeability of Cavb subunits interacting with differing Cav1 and Cav2 a1 subunit classes
The slowing of inactivation kinetics of invertebrate Cavb subunits occurs in the absence of the canonical palmitoylated residues found the N-terminus of vertebrate Cavb2a subunit, but notably the slowing of inactivation kinetics correlates with the presence of a stretch of polybasic residues at the 39 end of the HOOK domain common to vertebrate Cavb1 and Cavb2a subunits
Summary
Unique ancillary beta subunits are identifiable in the proteosomal complex with different voltage-gated ion channels including K [1,2,3], Na+ [4,5,6] and Ca2+ [7,8,9] channels. Calcium channel beta subunits (Cavb) have common homologs in animal groups rooted in genomes of single cell organisms like coanoflagellates, which possess an L-type calcium channel (Cav1) homolog [11]. From a likely primordial template of one Cav and Cavb subunit in coanoflagellates [12], emerged the complexity in numbers in vertebrates, where there are four different Cavb subunits, (b1, b2, b3, b4), which are expected to regulate seven pore-forming a1 subunits from the two high voltage-activated classes of calcium channels, Cav1.1–Cav1.4 (Ltype) and Cav2.1–Cav2.3 (non-L-type) [13]. There are low voltage-activated calcium channels, Cav3.1–Cav3.3 (T-type), but there is not strong evidence for their regulation by Cavb subunits [7]
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