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Molecular mechanism of the constitutive activity in the potassium ion channel complex important for potassium ion recycling in epithelial cells.
Go Kasuya, Koichi Nakajo

In the small intestine and trachea, transepithelial chloride ion secretion requires “potassium ion recycling”, a process that effluxes potassium ions which enter the epithelial cells upon the chloride transport. The KCNQ1-KCNE3 complex, composed of a voltage-gated potassium channel KCNQ1 and its auxiliary subunit KCNE3, is crucial for this process. While KCNQ1 opens and closes in a voltage-dependent manner, the KCNQ1-KCNE3 complex has a constitutively open nature at physiological voltages. However, the molecular mechanism of how KCNE3 protein makes KCNQ1 a constitutively open channel at physiological voltages is unknown. In this paper, by using electrophysiology and voltage clamp fluorometry, we found that the interaction between the S1 helix of KCNQ1 and KCNE3 is elaborately optimized to achieve the constitutively open nature. Since the malfunction of potassium ion recycling causes secretory diseases, including diarrhea, pulmonary edema, and cystic fibrosis, our findings facilitate understanding the pathogenesis of these secretory diseases.

Go Kasuya, Koichi Nakajo. Optimized tight binding between the S1 segment and KCNE3 is required for the constitutively open nature of the KCNQ1-KCNE3 channel complex. eLife : e81683, 2022.

<Figure Legends>
Molecular mechanism of constitutive activity in the KCNQ1-KCNE3 complex
A. Close-up view of the interface between KCNQ1 and KCNE3 in the KCNQ1-KCNE3 complex structure where the S1 helix of KCNQ1 interacts with the transmembrane region of KCNE3 (PDB:6V00).
B. The potassium-selective channel pore opens only when the distance between the S1 helix of KCNQ1 and the transmembrane region of KCNE3 is appropriate.

Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Japan