Distinct evolutionary trajectories of neuronal and hair cell nicotinic acetylcholine receptors

The expansion and pruning of ion channel families has played a crucial role in the evolution of nervous systems. Remarkably, with a highly conserved vertebrate complement, nicotinic acetylcholine receptors (nAChRs) are unique among ligand-gated ion channels in that distinct members of the family have non-overlapping roles in synaptic transmission, either in the nervous system, the inner ear hair cells or the neuromuscular junction. Here, we performed a comprehensive analysis of vertebrate nAChRs sequences, single cell expression patterns and comparative functional properties of receptors from three representative tetrapod species. We show that hair cell nAChRs underwent a distinct evolutionary trajectory to that of neuronal receptors. These were most likely shaped by different co-expression patterns and co-assembly rules of component receptor subunits. Thus, neuronal nAChRs showed high degree of coding sequence conservation, coupled to greater co-expression variance and conservation of functional properties across tetrapod clades. In contrast, hair cell α9α10 nAChRs exhibited greater sequence divergence, narrow co-expression pattern and great variability of functional properties across species. These results point to differential substrates for random change within the family of gene paralogs that relate to the segregated roles of nAChRs in synaptic transmission.