Evolutionary Analysis of Vertebrate KCNH Voltage-Gated Potassium Channels and Spatial Expression of kcnh Genes in Zebrafish Embryos.

Voltage-gated potassium channels (Kv) are a large family of potassium channels composed of 40 members across 12 subtypes. The KCNH genes encode three subfamilies of voltage-gated potassium channels: Kv10 (EAG, ether à go go), Kv11 (ERG, EAG-related gene), and Kv12 (ELK, EAG-like K). Kv channels play prominent roles in neuronal and cardiovascular systems. Mutations in Kv channels have been linked to many human diseases, such as epilepsy, heart arrhythmias, and cancers. Significant progress has been made in understanding protein structures, physiological functions, and pharmacological modifiers. However, the evolutionary history and gene expression of vertebrate KCNH genes during embryonic development remain largely unknown. We systematically identified and cloned 14 kcnh genes in zebrafish. Then, we examined the vertebrate KCNH channel evolution by phylogenetic and syntenic analyses. Our data reveal that the three subtypes of the KCNH gene family had already evolved in invertebrates, long before the emergence of vertebrates. The number of vertebrate KCNH genes increased, most likely due to whole-genome duplications (WGDs). In addition, we examined zebrafish kcnh gene expression during early embryogenesis by in situ hybridization. Each subgroup's genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues. Notably, kcnh6a showed robust expression in the developing heart, consistent with its conserved role in cardiac repolarization. Additionally, a few kcnh genes were transiently expressed in non-neural tissues, such as somites and the notochord, suggesting they may have a unique role in embryonic development. Our phylogenetic and developmental analyses of KCNH channels shed light on their evolutionary history and potential roles during embryogenesis, in line with their physiological functions and human channelopathies.