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PDZ domain mediated interactions with voltage-gated calcium (Ca ) channel C-termini play important roles in localizing and compartmentalizing membrane Ca signaling. The first such interaction discovered was between the neuronal multi-domain protein Mint-1, and the presynaptc calcium channel Ca 2.2 in mammals. Although the physiological significance of this interaction is unclear, its occurrence in vertebrates and bilaterian invertebrates suggests important and conserved functions. In this study, we explore the evolutionary origins of Mint and its interaction with Ca 2 channels. Phylogenetic and structural in silico analyses revealed that Mint is an animal-specific gene, like Ca 2 channels, which bears a highly divergent N-terminus but strongly conserved C-terminus comprised of a phosphotyrosine binding domain, two tandem PDZ domains (PDZ-1 and PDZ-2), and a C-terminal auto-inhibitory element that binds and inhibits PDZ-1. Also deeply conserved are other Mint interacting proteins, namely amyloid precursor and related proteins, presenilins, neurexin, as well as CASK and Veli which form a tripartite complex with Mint in bilaterians. Through yeast 2-hybrid and bacterial 2-hybrid experiments, we show that Mint and Ca 2 channels from cnidarians and placozoans interact , and hybridization revealed co-expression of corresponding transcripts in dissociated neurons from the cnidarian . Unexpectedly, the Mint orthologue from the ctenophore was able to strongly bind the divergent C-terminal ligands of cnidarian and placozoan Ca 2 channels, despite neither the ctenophore Mint, nor the placozoan and cnidarian orthologues, binding the ctenophore Ca 2 channel C-terminus. Altogether, our analyses provide a model for the emergence of this interaction in early animals first via adoption of a PDZ ligand by Ca 2 channels, followed by sequence changes in the ligand that caused a modality switch for binding to Mint.