KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions

Abstract

KCNE β-subunits assemble with and modulate the properties of voltage-gated K + channels. In the heart, KCNE1 associates with the α-subunit KCNQ1 to generate the slowly activating, voltagedependent potassium current (I Ks ) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K + channels that are voltageindependent K + channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-togate coupling.V oltage-gated K + (Kv) channels are mainly expressed in excitable cells, where changes in the voltage across the membrane, such as action potentials, demand rapid channel activation and deactivation. Among Kv channels, the KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that KCNQ1 plays key physiological roles in nonexcitable cells, such as in epithelia, in addition to its roles in excitable cells, such as cardiomyocytes. The KCNQ1 channels display dramatically different biophysical properties in various cell types, differences that are thought to be mainly due to the KCNQ1 channel's ability to associate with five tissue-specific KCNE β-subunits to form different K + channel complexes (1-7).KCNQ1 subunits expressed by themselves form voltage-dependent K + channels that open at negative voltages (1, 2) ( Fig. 1 A and D, black squares). However, coassembly of KCNQ1 with KCNE1 (also called MinK) produces a much slower activating potassium current (I Ks ) in the heart that activates at positive voltages ( Fig. 1 B and D, black triangles) and shapes the repolarization phase of cardiac action potentials (1, 2). Mutations in the KCNQ1/KCNE1 complex are linked to life-threatening cardiac arrhythmias, such as torsade de pointes (8, 9). Association of KCNQ1 with KCNE3 (also called MiRP2) produces channels that are voltage-independent in the physiological voltage range (Fig. 1 C and D, black circles) and that are crucial in regulating the transport of water and salt in several epithelial tissues, including the colon, small intestine, and airways (3, 10, 1...

Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

“…Different mechanisms have been proposed to explain how KCNE1 modulates KCNQ1 function including alteration of S4 movement ( Nakajo and Kubo, 2007 ; Rocheleau and Kobertz, 2008 ; Osteen et al, 2010 ; Ruscic et al, 2013 ; Barro-Soria et al, 2014 ), perturbation of gate opening ( Tapper and George, 2001 ; Melman et al, 2004 ; Panaghie et al, 2006 ), changes in VSD-PD coupling ( Zaydman et al, 2014 ; Westhoff et al, 2019 ), or a combination of these effects ( Nakajo and Kubo, 2014 ; Barro-Soria et al, 2017 ). However, a clear structural explanation is lacking owing to the absence of a high-resolution structure for the KCNQ1-KCNE1 complex.…”

“…Specifically, a three amino acid motif (F57-T58-L59, FTL) in the middle of the KCNE1 TMD ( Figure 1B ) was found to be necessary for induction of slow activation of KCNQ1 ( Melman et al, 2001 ; Melman et al, 2002 ). Replacement of the corresponding segment in KCNE3 (T71-V72-G73, TVG) with FTL confers KCNE1-like gating properties onto the KCNQ1-KCNE3 channel ( Barro-Soria et al, 2017 ; Melman et al, 2001 ; Melman et al, 2002 ). Likewise, mutation of FTL to TVG renders the KCNQ1-KCNE1 channel similar to KCNQ1-KCNE3, in that faster activation at more negative potentials is observed ( Barro-Soria et al, 2017 ; Melman et al, 2001 ).…”

“…Replacement of the corresponding segment in KCNE3 (T71-V72-G73, TVG) with FTL confers KCNE1-like gating properties onto the KCNQ1-KCNE3 channel ( Barro-Soria et al, 2017 ; Melman et al, 2001 ; Melman et al, 2002 ). Likewise, mutation of FTL to TVG renders the KCNQ1-KCNE1 channel similar to KCNQ1-KCNE3, in that faster activation at more negative potentials is observed ( Barro-Soria et al, 2017 ; Melman et al, 2001 ). How this so-called ‘activation motif’ determines the distinct gating properties of KCNQ1-KCNE channels is unclear.…”

Gene‐environment interaction in chronic kidney disease among people with type 2 diabetes from The Malaysian Cohort project: a case‐control study

“…Although genetic and environmental factors act independently of one another in the additive GxE model [13,14], their combined effect leads to significant synergistic interactions, resulting in higher CKD probability in our participants in the high-risk environment. This additive interaction could be due to the combination of the destructive effects on renal circulation exerted by smoking [17] and impaired renal haemodynamic balance, which is associated with KCNQ1 rs2237895 [22]. Obesity is associated with endothelial injury [23] and, coupled with vasoconstriction from reduced eNOS activity due to eNOS rs 2070744 [24], could cause a double hit on renal function.…”

A conserved arginine/lysine-based motif promotes ER export of KCNE1 and KCNE2 to regulate KCNQ1 channel activity

“…can also suppress the current amplitude of KCNQ1/ KCNE1 complex [7,8]. KCNE3 coassembles with KCNQ1 to confer constitutive activity [9,10]. KCNE4 and KCNE5 inhibit the channel activity of KCNQ1 [11,12].…”