Kv7.1 (KCNQ1) properties and channelopathies

Abstract

KCNQ1 is the pore-forming subunit of a channel complex whose expression and function have been rather well characterized in the heart. Almost 300 mutations of KCNQ1 have been identified in patients and a vast majority of the described mutations are linked to the long QT syndrome. Only a few mutations are linked to other pathologies such as atrial fibrillation and the short QT syndrome. However, a considerable amount of work remains to be done to get a clear picture of the molecular mechanisms responsible for the pathogenesis related to each mutation. The present review gives three examples of recent studies towards this goal and illustrates the diversity of the molecular mechanisms involved.

Figure 1. Ribbon structure diagram of the KCNQ1 structure in the N-terminal juxtamembranous domain, illustrating the potential effects of the L114P mutation on the structure of the trafficking determinant

The L114P mutation pulls apart Y111C from H126 located in the first transmembrane domain. The effect is highlighted in the cartoon on the right where WT KCNQ1 is shown in grey and L114P mutant in gold (see Material and Methods in Dahimene et al. 2006).

Figure 2. The effects of PIP₂ on KCNQ1–KCNE1 currents

Average time-dependent currents (I_rel) measured at the end of a 1 s depolarizing step to +40 mV relative to their maximum value measured after patch excision. Patches were excised in control solution (○, n = 9), control solution plus 1.4 mm MgATP (0.6 mm free Mg²⁺; •, n = 3), control solution plus 5 mg ml⁻¹ PIP₂ (dashed line, n = 5), control solution plus 1.4 mm MgATP plus 5 mg ml⁻¹ PIP₂ (▪, n = 9). (Figure adapted from Loussouarn et al. 2003; with permission.)

Figure 3. Dose–response relationship of the PIP₂ effects on WT and mutant KCNQ1–KCNE1 concatemer channels

Currents measured at the end of a 1 s depolarazing step to +80 mV relative to their maximum values extrapolated from a Hill fit. R243H, R539W and R555C mutants present a lower diC8-PIP₂ affinity than WT channels. (Figure adapted from Park et al. 2005; with permission.)