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Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy.

Moreau A, Gosselin-Badaroudine P, Delemotte L, Klein ML, Chahine M - J. Gen. Physiol. (2015)

Bottom Line: The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels.Two Na(v)1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy.Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Na(v)1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers.

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Affiliation: Centre de Recherche de L'Institut Universitaire en Santé Mentale de Québec, Québec City, Québec G1J 2G3, Canada.

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Gating pore current after long depolarizations. (A) Current generated by ramp pulses (see protocols in inset), for R222Q (left), R225W (middle), and WT (right) channels (using solutions 1 and 5 listed in Table 1). The I-V curves were constructed by averaging values of current at each 5 mV. The voltage was calculated using the known time course of the ramp protocol. Thus, for purpose of clarity, the plotted points (mean ± SEM) do not represent steady-state currents, but they represent average current every 5 mV. The linear leak subtraction around −75 to −45 mV was performed to eliminate inherent linear leak. The insets show the currents in response to ramp protocols. Dashed lines indicate the current obtained without 500-ms predepolarization. Solid lines indicate the response after 500-ms predepolarization. (B) Histogram summarizing the inward gating pore current density at −135 mV recorded with or without 500-ms predepolarization. R222Q and R225W exhibit gating pore currents when compared with control ramp protocols without predepolarization (−5.6 ± 1.1 pA/pF, n = 5, for R222Q [*], and −3.3 ± 0.6, n = 3, for R225W [#]). ++, statistical difference between mutant and WT condition (P < 0.01). Data are expressed as means ± SEM. Differences were considered significant at P < 0.05 (*, #) or < 0.01 (++).
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fig6: Gating pore current after long depolarizations. (A) Current generated by ramp pulses (see protocols in inset), for R222Q (left), R225W (middle), and WT (right) channels (using solutions 1 and 5 listed in Table 1). The I-V curves were constructed by averaging values of current at each 5 mV. The voltage was calculated using the known time course of the ramp protocol. Thus, for purpose of clarity, the plotted points (mean ± SEM) do not represent steady-state currents, but they represent average current every 5 mV. The linear leak subtraction around −75 to −45 mV was performed to eliminate inherent linear leak. The insets show the currents in response to ramp protocols. Dashed lines indicate the current obtained without 500-ms predepolarization. Solid lines indicate the response after 500-ms predepolarization. (B) Histogram summarizing the inward gating pore current density at −135 mV recorded with or without 500-ms predepolarization. R222Q and R225W exhibit gating pore currents when compared with control ramp protocols without predepolarization (−5.6 ± 1.1 pA/pF, n = 5, for R222Q [*], and −3.3 ± 0.6, n = 3, for R225W [#]). ++, statistical difference between mutant and WT condition (P < 0.01). Data are expressed as means ± SEM. Differences were considered significant at P < 0.05 (*, #) or < 0.01 (++).

Mentions: It was recently proposed that arginine mutations inside the VSD would cause a loss of mobility (or a partial freezing) of the S4 after long depolarization periods (Sokolov et al., 2008; Fan et al., 2013; Groome et al., 2014). In the presence of 10 µM TTX, a 500-ms predepolarization was used to mimic the cardiac AP duration. We then applied a ramp protocol from −140 to 0 mV at 0.72 mV/ms to measure gating pore current (see protocol in inset of Fig. 6). At hyperpolarized potentials, gating pore currents were observed after a long depolarization for both R222Q and R225W mutations (−5.6 ± 1.1 pA/pF, n = 5, for R222Q and −3.3 ± 0.6, n = 3, for R225W) and were absent for the WT (−0.9 ± 0.1 pA/pF, n = 5). Such currents could not be observed without the 500-ms predepolarization (Fig. 6). These results show that after long depolarization periods, the mutated S4 segments need more time to resume their resting position and thus partially remain in a conformation, likely enabling gating pore current conduction.


Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy.

Moreau A, Gosselin-Badaroudine P, Delemotte L, Klein ML, Chahine M - J. Gen. Physiol. (2015)

Gating pore current after long depolarizations. (A) Current generated by ramp pulses (see protocols in inset), for R222Q (left), R225W (middle), and WT (right) channels (using solutions 1 and 5 listed in Table 1). The I-V curves were constructed by averaging values of current at each 5 mV. The voltage was calculated using the known time course of the ramp protocol. Thus, for purpose of clarity, the plotted points (mean ± SEM) do not represent steady-state currents, but they represent average current every 5 mV. The linear leak subtraction around −75 to −45 mV was performed to eliminate inherent linear leak. The insets show the currents in response to ramp protocols. Dashed lines indicate the current obtained without 500-ms predepolarization. Solid lines indicate the response after 500-ms predepolarization. (B) Histogram summarizing the inward gating pore current density at −135 mV recorded with or without 500-ms predepolarization. R222Q and R225W exhibit gating pore currents when compared with control ramp protocols without predepolarization (−5.6 ± 1.1 pA/pF, n = 5, for R222Q [*], and −3.3 ± 0.6, n = 3, for R225W [#]). ++, statistical difference between mutant and WT condition (P < 0.01). Data are expressed as means ± SEM. Differences were considered significant at P < 0.05 (*, #) or < 0.01 (++).
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fig6: Gating pore current after long depolarizations. (A) Current generated by ramp pulses (see protocols in inset), for R222Q (left), R225W (middle), and WT (right) channels (using solutions 1 and 5 listed in Table 1). The I-V curves were constructed by averaging values of current at each 5 mV. The voltage was calculated using the known time course of the ramp protocol. Thus, for purpose of clarity, the plotted points (mean ± SEM) do not represent steady-state currents, but they represent average current every 5 mV. The linear leak subtraction around −75 to −45 mV was performed to eliminate inherent linear leak. The insets show the currents in response to ramp protocols. Dashed lines indicate the current obtained without 500-ms predepolarization. Solid lines indicate the response after 500-ms predepolarization. (B) Histogram summarizing the inward gating pore current density at −135 mV recorded with or without 500-ms predepolarization. R222Q and R225W exhibit gating pore currents when compared with control ramp protocols without predepolarization (−5.6 ± 1.1 pA/pF, n = 5, for R222Q [*], and −3.3 ± 0.6, n = 3, for R225W [#]). ++, statistical difference between mutant and WT condition (P < 0.01). Data are expressed as means ± SEM. Differences were considered significant at P < 0.05 (*, #) or < 0.01 (++).
Mentions: It was recently proposed that arginine mutations inside the VSD would cause a loss of mobility (or a partial freezing) of the S4 after long depolarization periods (Sokolov et al., 2008; Fan et al., 2013; Groome et al., 2014). In the presence of 10 µM TTX, a 500-ms predepolarization was used to mimic the cardiac AP duration. We then applied a ramp protocol from −140 to 0 mV at 0.72 mV/ms to measure gating pore current (see protocol in inset of Fig. 6). At hyperpolarized potentials, gating pore currents were observed after a long depolarization for both R222Q and R225W mutations (−5.6 ± 1.1 pA/pF, n = 5, for R222Q and −3.3 ± 0.6, n = 3, for R225W) and were absent for the WT (−0.9 ± 0.1 pA/pF, n = 5). Such currents could not be observed without the 500-ms predepolarization (Fig. 6). These results show that after long depolarization periods, the mutated S4 segments need more time to resume their resting position and thus partially remain in a conformation, likely enabling gating pore current conduction.

Bottom Line: The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels.Two Na(v)1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy.Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Na(v)1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre de Recherche de L'Institut Universitaire en Santé Mentale de Québec, Québec City, Québec G1J 2G3, Canada.

Show MeSH
Related in: MedlinePlus