This work explores the evolutionary origins of the sodium leak channel NALCN and its ancillary subunits FAM155/Mid1, UNC79, and UNC80. We uncover ancient o

The authors generated a species-guided phylogeny of eukaryotic iGluRs, alongside a focused analysis of iGluR homologues from the early-branching invertebrate phylum Placozoa.

Monoamines are biologically active compounds crucial for neurotransmission and various physiological processes. They include neurotransmitters like serotonin, dopamine, and melatonin, which regulate mood, movement, and sleep in humans. In ecdysozoans, monoamines such as tyramine are important for modulating locomotion, learning, and feeding. The monoaminergic signalling system has been considered a bilaterian innovation, with conflicting evidence supporting its existence in earlier branching, non-bilaterian animals. Here, we challenge the bilaterian origin hypothesis by combining large-scale receptor deorphanisation with phylogenetic analyses to identify monoamine receptors from the placozoan Trichoplax adhaerens. We demonstrate that these receptors are homologous to known bilaterian GPCRs, and behavioural assays demonstrate that monoamines like tyramine and tryptamine affect the speed of locomotion and body shape of this animal, respectively. These responses, together with the presence of biosynthetic enzymes for these molecules, reveal that monoaminergic signalling is both active and endogenous in placozoans. Our findings provide compelling evidence for a prebilaterian origin of monoaminergic systems, reshaping our understanding of early nervous system evolution. ### Competing Interest Statement The authors have declared no competing interest.

The sodium leak channel NALCN, a key regulator of neuronal excitability, associates with three ancillary subunits that are critical for its function: an extracellular subunit called FAM155, and two cytoplasmic subunits called UNC79 and UNC80. Interestingly, NALCN and FAM155 have orthologous phylogenetic relationships with the fungal calcium channel Cch1 and its extracellular subunit Mid1, however, UNC79 and UNC80 have not been reported outside of animals. In this study, we leveraged expanded gene sequence data available for eukaryotes to re-examine the evolutionary origins of NALCN and Cch1 channel subunits. Our analysis corroborates the direct phylogenetic relationship between NALCN and Cch1 and identifies a larger clade of related channels in additional eukaryotic taxa. We also identify homologues of FAM155/Mid1 in Cryptista algae, and UNC79 and UNC80 homologues in numerous non-metazoan eukaryotes including basidiomycete and mucoromycete fungi, and the microbial eukaryotic taxa Apusomonadida, Malawimonadida, and Discoba. Furthermore, we find that most major animal lineages, except ctenophores, possess a full complement of NALCN subunits. Comparing structural predictions with the solved structure of the human NALCN complex supports orthologous relationships between metazoan and non-metazoan FAM155/Mid1, UNC79, and UNC80 homologues. Together, our analyses reveal unexpected diversity and ancient eukaryotic origins of NALCN/Cch1 channelosome subunits and raise interesting questions about the functional nature of this conserved channel complex within a broad, eukaryotic context. ### Competing Interest Statement The authors have declared no competing interest.

Ligand-gated ion channels (LGICs) are critical for neurotransmission, mediating responses to neurotransmitters and hormones, and influencing diverse p…

The advent of droplet-based single-cell RNA-sequencing (scRNA-seq) has dramatically increased data throughput, enabling the release of a diverse array of tissue cell atlases to the public. However, we...

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