Voltage-Dependent Gating: Novel Insights from KCNQ1 Channels

Abstract

Gating of voltage-dependent cation channels involves three general molecular processes: voltage sensor activation, sensor-pore coupling, and pore opening. KCNQ1 is a voltage-gated potassium (Kv) channel whose distinctive properties have provided novel insights on fundamental principles of voltage-dependent gating. 1) Similar to other Kv channels, KCNQ1 voltage sensor activation undergoes two resolvable steps; but, unique to KCNQ1, the pore opens at both the intermediate and activated state of voltage sensor activation. The voltage sensor-pore coupling differs in the intermediate-open and the activated-open states, resulting in changes of open pore properties during voltage sensor activation. 2) The voltage sensor-pore coupling and pore opening require the membrane lipid PIP2 and intracellular ATP, respectively, as cofactors, thus voltage-dependent gating is dependent on multiple stimuli, including the binding of intracellular signaling molecules. These mechanisms underlie the extraordinary KCNE1 subunit modification of the KCNQ1 channel and have significant physiological implications.

Figure 1

Models of the KCNQ1 channel. (A) Top view of the tetrameric KCNQ1 homology model. Four subunits are shown in different colors. Every subunit consists S1–S6 transmembrane segments as indicated. The S1–S4 form the voltage sensor domain, and the S5-S6 from all four subunits form the pore-gate domain. This open state KCNQ1 structural model is originated from Van Horn et al. (4). (B) Side view of the KCNQ1 channel homology model; the selectivity filter is labeled as indicated. (C) Membrane topology of full length KCNQ1. Each circle represents an amino acid residue with the one-letter symbol. The S1–S6 and cytoplasmic C terminus helices (A–D) are labeled as indicated. The residues important for voltage-dependent gating, including the gating charges in S4 (R1, R2, and R4), E160 in S2, F351 in the cytoplasmic end of S6, and the PIP₂ and ATP binding sites are colored as indicated.