The membrane protein KCNQ1 potassium ion channel: Functional diversity and current structural insights

Abstract

Background: Ion channels play crucial roles in cellular biology, physiology, and communication including sensory perception. Voltage-gated potassium (Kv) channels execute their function by sensor activation, pore-coupling, and pore opening leading to K⁺ conductance.

Scope of review: This review focuses on a voltage-gated K⁺ ion channel KCNQ1 (Kv 7.1). Firstly, discussing its positioning in the human ion chanome, and the role of KCNQ1 in the multitude of cellular processes. Next, we discuss the overall channel architecture and current structural insights on KCNQ1. Finally, the gating mechanism involving members of the KCNE family and its interaction with non-KCNE partners.

Major conclusions: KCNQ1 executes its important physiological functions via interacting with KCNE1 and non-KCNE1 proteins/molecules: calmodulin, PIP₂, PKA. Although, KCNQ1 has been studied in great detail, several aspects of the channel structure and function still remain unexplored. This review emphasizes the structural and biophysical studies of KCNQ1, its interaction with KCNE1 and non-KCNE1 proteins and focuses on several seminal findings showing the role of VSD and the pore domain in the channel activation and gating properties.

General significance: KCNQ1 mutations can result in channel defects and lead to several diseases including atrial fibrillation and long QT syndrome. Therefore, a thorough structure-function understanding of this channel complex is essential to understand its role in both normal and disease biology. Moreover, unraveling the molecular mechanisms underlying the regulation of this channel complex will help to find therapeutic strategies for several diseases.

Keywords: Channelopathy; Chanome; KCNE1; KCNQ1; Long QT syndrome; Potassium ion channel.

Figure 1.

(A) Ion-channel chanome depicting voltage-gated ion channel superfamily with different sub-classes. (B) Floral diagram depiction of human potassium ion channel (Kv) superfamily and the relative position of KCNQ1 (Kv 7.1) in the channel superfamily.

Figure 2.

(A) Physiological roles of KCNQ1 in human body (Figure design inspired from Liin et al.; ref. 33). (B) mutated or dysfunctional KCNQ1 is associated with various diseases.

Figure 3.

Topological depiction of KCNQ1 in a membrane environment.

Figure 4.

(A) Membrane topology of KCNQ1-Voltage Sensor Domain (Q1-VSD) showing the movement of S4 helix during VSD activation. (B) Important role played by KCNQ1–S6 and S4 helices and their interaction with KCNE1 and KCNE3 (depited as E1 and E3 (yellow) in 4B and 4C respectively) proteins in the opening/closing (gating mechanism) of the channel complex.

Figure 5.

(A) KCNQ1-KCNE1 channel complex, where each subunit of KCNQ1 is labeled as 1–4 and S1–S6 helices of KCNQ1 are shown in different colors. (B) Top cartoon view of the complex showing VSD in the cleft between KCNQ1 and KCNE1 (shown as E1 in red) monomers. The pore domain is surrounded by blue colored S5–S6 helices.