Evolutionary acquisition and divergence of vertebrate HCN2 palmitoylation

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control rhythmic activity in mammalian nervous system and heart. Among four HCN family isoforms (HCN1-4), mouse HCN2 is specifically palmitoylated at five cysteine residues in its N-terminus. Here, we further focused on conservation of these palmitoylation sites found in vertebrate HCN2 orthologs. Analysis of sequence databases provided an insight into stepwise acquisition of HCN2 palmitoylation motifs in vertebrate lineages. The mechanism of HCN2 palmitoylation itself has been broadly conserved throughout vertebrate species in spite of the divergence of HCN2 full-length amino acid sequences during molecular evolution. Furthermore, there exist vertebrate class-specific variation of palmitoylation motifs. Our findings mean that dynamic regulation of HCN2 made possible by reversible post-translational protein palmitoylation may be critical for refined functions of the vertebrate nervous system and heart.