Physiology and Evolution of Voltage-Gated Calcium Channels in Early Diverging Animal Phyla: Cnidaria, Placozoa, Porifera and Ctenophora

Abstract

Voltage-gated calcium (Cav) channels serve dual roles in the cell, where they can both depolarize the membrane potential for electrical excitability, and activate transient cytoplasmic Ca2+ signals. In animals, Cav channels play crucial roles including driving muscle contraction (excitation-contraction coupling), gene expression (excitation-transcription coupling), pre-synaptic and neuroendocrine exocytosis (excitation-secretion coupling), regulation of flagellar/ciliary beating, and regulation of cellular excitability, either directly or through modulation of other Ca2+-sensitive ion channels. In recent years, genome sequencing has provided significant insights into the molecular evolution of Cav channels. Furthermore, expanded gene datasets have permitted improved inference of the species phylogeny at the base of Metazoa, providing clearer insights into the evolution of complex animal traits which involve Cav channels, including the nervous system. For the various types of metazoan Cav channels, key properties that determine their cellular contribution include: Ion selectivity, pore gating, and, importantly, cytoplasmic protein-protein interactions that direct sub-cellular localization and functional complexing. It is unclear when these defining features, many of which are essential for nervous system function, evolved. In this review, we highlight some experimental observations that implicate Cav channels in the physiology and behavior of the most early-diverging animals from the phyla Cnidaria, Placozoa, Porifera, and Ctenophora. Given our limited understanding of the molecular biology of Cav channels in these basal animal lineages, we infer insights from better-studied vertebrate and invertebrate animals. We also highlight some apparently conserved cellular functions of Cav channels, which might have emerged very early on during metazoan evolution, or perhaps predated it.

Early metazoan origin and multiple losses of a novel clade of RIM pre-synaptic calcium channel scaffolding protein homologues

“…The apparent absence of synapses in Trichoplax is not reflected by its expressed gene set, which in addition to RIM includes homologues for key active zone proteins such as SNARE and associated proteins, and scaffolding proteins that interact with Ca V 2 calcium channels at nerve terminals such as Mint, CASK, Liprin-α, ELKS and RIM-BP (Figure 1A and B). Trichoplax is also the most early-diverging animal with homologues for all three metazoan Ca V channel types: Ca V 1, Ca V 2 and Ca V 3 (Senatore, et al 2012; Moran and Zakon 2014; Senatore, et al 2016; Smith, et al 2017).…”

“…Nevertheless, a comprehensive analysis of Ca V channel C-terminal sequences within the Metazoa, to explore conservation of C-terminal PDZ ligand motifs, has not been reported. Furthermore, recently sequenced genomes and transcriptomes permit re-exploration of the Ca V channel phylogeny (Moran and Zakon 2014; Senatore, et al 2016). Hence, using sequences compiled from genomic and transcriptomic databases, we constructed a comprehensive maximum likelihood protein phylogeny of various Ca V α subunits, and aligned their 10 distal-most C-terminal amino acid sequences which would bear putative PDZ ligand motifs (Figure 5A).…”

“…Indeed, Ca V channels are known to drive synaptic transmission in cnidarians (Bullock 1943; Kerfoot, et al 1985). However, whether they similarly exhibit nanodomain and microdomain synapses, distinguished by the proximity between Ca V channels and synaptic vesicle Ca 2+ sensors, is not known (Senatore, et al 2016).…”

“…Nevertheless, we note broad conservation of predicted N-terminal alpha-helical structures associated with Rab3 binding (Figure S2, Supplementary file 1), suggesting that II-RIMs can interact with vesicles. To our knowledge, ctenophores are the only animals in which the requirement for pre-synaptic Ca 2+ influx for exocytosis and synaptic transmission has not yet been confirmed, and little is known about the mechanisms for synaptic transmission in these animals (Senatore, et al 2016). However, microscopy studies have revealed structures with hallmark features of synapse active zones (Hernandez-Nicaise 1973), and ctenophores possess Ca V 2 channels.…”

“…Recently, low-voltage activated (LVA) T-type (Ca V 3) channels have also been shown to interact with the Ca V β subunit (Bae, et al 2010), as well as calmodulin (Chemin, et al 2017), though they lack AID and IQ motifs. Concomitant to phylogenetic, biophysical and pharmacological distinctions between Ca V 1-Ca V 3 channels, it is apparent that distinct sets of interacting proteins are integral to their unique functions in different cell types, which appear broadly conserved in the Metazoa (Senatore, et al 2016).…”