Mutant analysis of Kcng4b reveals how the different functional states of the voltage-gated potassium channel regulate ear development
Author:
Jędrychowska Justyna, Vardanyan Vitya, Wieczor Milosz, Marciniak Antoni, Czub Jacek, Amini Razieh, Jain Ruchi, Shen Hongyuan, Choi HyungwonORCID, Kuznicki Jacek, Korzh VladimirORCID
Abstract
AbstractThe voltage gated (Kv) slow-inactivating delayed rectifier channel regulates the development of hollow organs of the zebrafish. The functional tetramer consists of an electrically active subunit (Kcnb1, Kv2.1) and a modulatory silent subunit (Kcng4b, Kv6.4). The two mutations in zebrafishkcng4b - kcng4b-C1andkcng4b-C2(Gasanov et al., 2021) - have been studied during ear development using electrophysiology, developmental biology andin silicostructural modelling.kcng4b-C1mutation causes a C-terminal truncation characterized by mild Kcng4b loss-of-function (LOF) manifested by failure of kinocilia to extend and formation of ectopic otoliths. In contrast, thekcng4b-C2-/-mutation causes the C-terminal domain to elongate and the ectopic seventh transmembrane (TM) domain to form, converting the intracellular C-terminus to an extracellular one. Kcng4b-C2 acts as a Kcng4b gain-of-function (GOF) allele. Otoliths fail to develop and kinocilia are reduced inkcng4b-C2-/-. These results show that different mutations of the silent subunit Kcng4 can affect the activity of the Kv channel and cause a wide range of developmental defects.
Publisher
Cold Spring Harbor Laboratory
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