Voltage sensor inactivation in potassium channels

Abstract

In voltage-gated potassium (Kv) channels membrane depolarization causes movement of a voltage sensor domain. This conformational change of the protein is transmitted to the pore domain and eventually leads to pore opening. However, the voltage sensor domain may interact with two distinct gates in the pore domain: the activation gate (A-gate), involving the cytoplasmic S6 bundle crossing, and the pore gate (P-gate), located externally in the selectivity filter. How the voltage sensor moves and how tightly it interacts with these two gates on its way to adopt a relaxed conformation when the membrane is depolarized may critically determine the mode of Kv channel inactivation. In certain Kv channels, voltage sensor movement leads to a tight interaction with the P-gate, which may cause conformational changes that render the selectivity filter non-conductive ("P/C-type inactivation"). Other Kv channels may preferably undergo inactivation from pre-open closed-states during voltage sensor movement, because the voltage sensor temporarily uncouples from the A-gate. For this behavior, known as "preferential" closed-state inactivation, we introduce the term "A/C-type inactivation". Mechanistically, P/C- and A/C-type inactivation represent two forms of "voltage sensor inactivation."

Keywords: Kv channels; P/C-type inactivation; U-type inactivation; closed-state inactivation.

Figure 1

Formal description of Kv channel gating. (A) Scheme 1: Simplified gating scheme which represents a classical view of inactivation from open and closed-states (C_R, resting state; C*, activated but still closed-state; O, open state; I_N, N-type inactivated state; I_P/C, P/C-type inactivated state; I_N,P/C, N-type and P/C-type inactivated state; I_C, closed-inactivated state). The voltage-sensitive transition is indicated (ΔV). (B) Scheme 2: Extended gating scheme adopted from Kaulin et al. (2008), which accounts for the activation pathway of a tetrameric channel accompanied by two inactivation pathways based on different mechanisms (C, closed-states; A, inactivated states involving the A-gate; P, inactivated states involving the P-gate; suffix R means “resting,” suffixes 1–4 represent number of subunits in this state, suffix 5 denotes states which precede a concerted opening step; O, open state). The voltage-sensitive transitions are indicated (ΔV). Collectively, A-states represent preferential closed-state inactivation (CSI) or “A/C-type inactivation”; P-states represent P/C-type inactivation, P₁–P₅ from closed-states, P₆ from the open state.

Figure 2

Models of voltage-dependent activation and voltage sensor inactivation in Kv channels. Cartoons illustrate putative conformations a single Kv channel α-subunit may adopt in a subtype-specific manner when the membrane encounters prolonged depolarization. (A) Resting state; the voltage sensor is in its resting position (down) and the channel is closed (S1–S6, transmembrane segments; P-gate, pore gate with selectivity filter; A-gate, activation gate represented by the distal S6 segment, which is involved in the bundle crossing in the tetramer). (B) Open conducting state; the voltage sensor is activated (up) and the channel is open (green arrow denotes putative opening motion of the A-gate). (C) Open but non-conducting state; the voltage sensor has adopted a relaxed conformation (blue) which tightly interacts with the P-gate rendering the selectivity filter non-conducting (red). (D) Closed-inactivated state with the A-gate uncoupled (red); the voltage sensor has adopted a relaxed conformation (blue), and the A-gate is closed (A/C-type inactivation). (E) Closed-inactivated state with the P-gate in its non-conductive conformation (red); the voltage sensor has adopted a relaxed conformation (blue), the A-gate is still coupled to the voltage sensor but the channel has not opened (P/C-type inactivation of a closed channel).