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

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

Adriano Senatore et al. Front Physiol.

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.

Keywords: calcium channel evolution; early-diverging animals; evolution of the nervous system; excitation-contracting coupling; pre-synaptic exocytosis; regulation of ciliary beating; synapse evolution; synaptic scaffolding.

Figures

Figure 1
Figure 1
Leading phylogeny of early-diverging animal phyla. The two alternate hypotheses for nervous system are depicted. The single origin hypothesis involves emergence at the stem of Metazoa (blue vertical bar), and losses in both Porifera (sponges) and Placozoa (Trichoplax; blue crosses), whereas the independent origins hypotheses involves separate emergence in Ctenophora (comb jellies) vs. Cnidaria (jellyfish, sea anemones, corals) and Bilateria (animals with bilateral symmetry; red vertical bars).
Figure 2
Figure 2
(A) Illustration of the membrane topology of P-loop Cav1 (L-type) and Cav2 (N-, P/Q-, and R-type) channels, depicting their HVA selectivity filter motifs of EEEE. Voltage sensor S1–S4 helices are colored red, and pore-forming S5 and S6 helices bearing the pore-loops orange. HVA channels interact with the cytoplasmic Cavβ subunit via the alpha interaction domain (AID) in the domain I-II linker, and the Cavα2δ subunit which is anchored to the membrane and projects to the extracellular space. (B) Cav3 (T-type channels) bear EEDD selectivity filters, do not interact with Cavβ and Cavα2δ subunits, and in place of the AID bear helix-loop helix gating brake structures.
Figure 3
Figure 3
(A) Protein sequence alignment of domain I to IV S4 helices from Cav channel voltage sensors, depicting the strong conservation of positively charged lysine (K) and arginine (R) residues critical for voltage sensitivity. (B) Alignment of selectivity filter motifs and flanking amino acids from various Cav channel proteins, revealing conserved EEEE motifs for Cav1, Cav2, and Cav1/2 channels, and EEDD for Cav3 channels. (C) Protein sequence alignment of C-terminal IQ motifs found in Cav1, Cav2, and Cav1/2 channel types.
Figure 4
Figure 4
Maximum likelihood protein phylogeny of select Cav channels from animals, rooted with Cav channel homologs from fungi. Inference was achieved using MUSCLE protein alignment with MEGA7, followed by alignment trimming with TrimAL. Evolutionary models for maximum likelihood phylogenetic inference were tested with MEGA7, indicating that the LG matrix with gamma frequencies was the best fit using both corrected Akaike's Information Criterion and Bayesian Information Criterion. Node support values from 500 bootstrap replicates are indicated. GenBank accession numbers: Salpingoeca Cav1/Cav2: XP_004989719; Amphimedon Cav1/Cav2: XP_003383036; Trichoplax Cav1: XP_002108930; Trichoplax Cav2: XP_002109775; Trichoplax Cav3: KJ466205; C.elegans Cav1 (egl-19): NP_001023079; C.elegans Cav2 (unc-2): NP_001123176; C.elegans Cav3 (cca-1): CCD68017; Drosophila Cav1 (α1-D): AAF53504; Drosophila Cav2 (cacophony): AFH07350; Drosophila Cav3 (Ca-α1T): ABW09342; Lymnaea Cav1: AAO83839; Lymnaea Cav2: AAO83841; Lymnaea Cav3: AAO83843; human Cav1.1: NP_000060.2; human Cav1.2: AAI46847.1; human Cav1.3: NP_001122312.1; human Cav1.4: NP_005174.2; human Cav2.1: O00555.2; human Cav2.2: NP_000709; human Cav2.3: NP_001192222.1; human Cav3.1: NP_061496; human Cav3.2: NP_066921; human Cav3.3: NP_066919; Mnemiopsis Cav2: AEF59085; S.cerevisae CCH1: P50077; S.pombe CCH1: NP_593894.1. Other accession numbers: Nematostella Cav1: JGI-Genome Portal protein ID 88037; Nematostella Cav2a, Cav2b, Cav2c, Cav3a, Cav3b: Transcript sequences from the sequenced transcriptome (Fredman et al., 2013) NVE4667, NVE18768, NVE1263, NVE5017, and NVE7616 respectively. Scale bar represents the number of amino acid substitutions per site along the sequence alignment.
Figure 5
Figure 5
(A) Dorsal view of Trichoplax adhaerens photographed through a stereomicroscope, revealing its irregularly-shaped body lacking symmetry outside of dorsal-ventral polarity. Gland cells are located in the ventral epithelium, most concentrated along the outside rim (i.e., within the darker band visible in the image). Scale bar is 200 μm. (B) Whole cell patch-clamp recorded Ca2+ currents of the cloned Trichoplax Cav3 channel expressed in HEK-293T cells, bearing rapid activation and inactivation kinetics, and a crossing over of current traces during inactivation with increasing depolarization (recorded in 2 mM external Ca2+ solution). (C) Current-voltage plot of average normalized peak inward Ca2+ current of Trichoplax Cav3, revealing its low voltage of activation with peak inward current at −45 mV (n = 10, error bars indicate SE from the mean). (D) Bar graph of mean mRNA expression levels of select Trichoplax ion channel genes and their subunits estimated with the program eXpress (Roberts and Pachter, 2013), quantified as transcripts per million (TPM) from assembled transcriptome data and four separate Illumina sequencing datasets of whole animal poly(A)-extracted mRNA (2x125 base pair reads; manuscript in preparation). Channels were identified via BLAST homology with mammalian protein sequences using an expect value cut-off of 1 x 10−5. Two ubiquitously expressed genes, Hypoxanthine Phosphoribosyltransferase 1 (HPRT1) and Succinate Dehydrogenase A (SDHA), are included as reference genes. Error bars indicate standard error from the mean TPM expression.
Figure 6
Figure 6
(A) Illustration of a cydippid ctenophore, showing the oral and aboral poles bearing the mouth (m) and statocyst (sc), respectively. Ctenophores possess eight comb rows (cr), each made up of a series of comb plates (cp) which beat in the oral-aboral direction during forward swimming, or aboral-oral direction during reverse and rotational swimming. Geotactic control of comb row beating occurs via signal transduction from the statocyst, a ciliated gravitometric organ, to the beginning of each comb row via ciliated grooves (cg). Tentacles (t) and tentilla (tl) bear colloblasts, laden with adhesive granules used for prey capture; injested food enters the mouth into the pharynx (p), and eventually the stomach (s) and digestive system. Inset: Side view of two balancers (b) of the statocyst of an animal in the horizontal position, connected at their tips to the statolith (sl). Weight from the statolith mechanically deflects the balancers either toward or away from the midline (m), mechanically activating the beating of balancer cilia; these then activate waves of beating in the ciliated grooves (cg) which propagate to the comb rows. (B) Illustration of the pre-synaptic triad of ctenophore synapses, consisting of rows of synaptic vesicles (sv) arranged along the membrane, adjacent to a finger-like projection of smooth endoplasmic reticulum, which lacks ribosomes (r) of the rough endoplasmic reticulum, and one or several large mitochondria (mi). n, nucleus; g, Golgi, c.v, cytoplasmic vesicles; co, post-synaptic dense coat; p, pre-synaptic dense projections. Reprinted with permission from Hernandez-Nicaise (1973a).

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