Abstract
The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. Given the overlapping functional properties of CaV2 and CaV1 channels, and less so CaV3 channels, it is unclear why there have not been major shifts toward dependence on other CaV channels for synaptic transmission. Here, we provide a structural and functional profile of the CaV2 channel cloned from the early-diverging animal Trichoplax adhaerens, which lacks a nervous system but possesses single gene homologues for CaV1–CaV3 channels. Remarkably, the highly divergent channel possesses similar features as human CaV2.1 and other CaV2 channels, including high voltage–activated currents that are larger in external Ba2+ than in Ca2+; voltage-dependent kinetics of activation, inactivation, and deactivation; and bimodal recovery from inactivation. Altogether, the functional profile of Trichoplax CaV2 suggests that the core features of presynaptic CaV2 channels were established early during animal evolution, after CaV1 and CaV2 channels emerged via proposed gene duplication from an ancestral CaV1/2 type channel. The Trichoplax channel was relatively insensitive to mammalian CaV2 channel blockers ω-agatoxin-IVA and ω-conotoxin-GVIA and to metal cation blockers Cd2+ and Ni2+. Also absent was the capacity for voltage-dependent G-protein inhibition by co-expressed Trichoplax Gβγ subunits, which nevertheless inhibited the human CaV2.1 channel, suggesting that this modulatory capacity evolved via changes in channel sequence/structure, and not G proteins. Last, the Trichoplax channel was immunolocalized in cells that express an endomorphin-like peptide implicated in cell signaling and locomotive behavior and other likely secretory cells, suggesting contributions to regulated exocytosis.
Highlights
The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved
A maximum likelihood protein phylogeny of various CaV2 channels exhibited complete lineage sorting with respect to the leading metazoan phylogeny [51], with Trichoplax CaV2 (TCaV2) and the CaV2 channel homologue from fellow placozoan H. hongkongensis forming a sister relationship with cnidarian and bilaterian CaV2 channels (Fig. 1B) and homologues from ctenophores forming the most distant clade of CaV2 channels
Our work here characterizing the functional properties of the CaV2 channel from T. adhaerens revealed that despite upwards of 600 million years of divergence, TCaV2 conducts high voltage–activated Ca21 currents with similar profiles to those of human CaV2.1 and other cloned CaV2 channels [2, 6], such as the homologues from the snail L. stagnalis [37] and the honeybee Apis mellifera [102]
Summary
The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. We provide a structural and functional profile of the CaV2 channel cloned from the early-diverging animal Trichoplax adhaerens, which lacks a nervous system but possesses single gene homologues for CaV1–CaV3 channels. Despite lacking synapses, increasing evidence suggests that cellular communication in placozoans likely occurs in a protosynaptic manner, where regulated secretion of signaling molecules, such as neuropeptides and small-molecule transmitters, targets membrane receptors on other cells to exert an effect [18, 21, 23, 24] In addition to their distinct voltages of activation, CaV channels are distinguished by their differential association with accessory CaVb and CaVa2d subunits, which are essential for the proper membrane expression and function of CaV1 and CaV2, but not CaV3 channels [2, 6]. Their cellular functions overlap in certain contexts, there are
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