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. 2019 Dec 27;9:19825. doi: 10.1038/s41598-019-56081-y

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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hERG1a- and 1b-mediated current is inhibited by extracellular acidosis. (ai) HERG1a-mediated current evoked by the protocol in inset is reduced in amplitude and current deactivation is accelerated by addition of extracellular solution with a pH of 6.3. (aii and iii) Extracellular acidification causes a shift in voltage-dependence of activation of hERG1a-mediated current, with V_0.5 of −10.0 ± 1.2 mV (k = 6.8 ± 0.2 mV) at pH 7.4 (n = 15 cells) shifted to a V_0.5 of −7.0 ± 2.8 mV (k = 8.3 ± 1.1 mV) at pH 6.3 (n = 8 cells). (aii) Shows mean current-voltage (I–V) relations for I_hERG tails at pH 7.4 and 6.3, expressed in pA/pF, whilst in (aiii) currents following each test potential were normalized to the maximum current (I_max) elicited by the protocol. (aiv) Graphs showing acceleration by acidic pH_e of the two time -course components of hERG1a-mediated current with hyperpolarization. Data are shown as mean ± S.E.M for the fast time constant (τ_Fast) (left) at pH 7.4 (•)(n = 15 cells) and 6.3 (○)(n = 8 cells) and slow time constant (τ_Slow) (right) of deactivation at pH 7.4 (•)(n = 15 cells) and 6.3 (○)(n = 8 cells). The fast component of current deactivation changed e-fold in 26 mV. Application of pH 6.3 accelerated the fast time component without affecting apparent voltage dependence. In contrast, the slow component of deactivation changed e-fold in 20 mV, with pH 6.3 solution increasing the rate of this component and reducing the apparent voltage dependence to e-fold in 30 mV. ‘*’, ‘**’, ‘***’, and ‘****’ denote statistical significance of P < 0.05, P < 0.01, P < 0.001 and P < 0.0001 respectively (2-way ANOVA with Bonferroni post-test). (bi) hERG1b-mediated current (same protocol as hERG1a) was reduced in amplitude and current deactivation is accelerated by addition of extracellular solution with a pH of 6.3. (bii and iii) The voltage dependence of activation of hERG1b-mediated current was significantly positively shifted, with the V_0.5 value changing from −16.2 ± 2.8 mV (k = 7.6 ± 0.6 mV) at pH 7.4 (n = 7 cells) to a V_0.5 of +2.2 ± 1.1 mV (k = 12.6 ± 1.0 mV) at pH 6.3 (n = 7 cells). (bii) Shows mean current-voltage (I–V) relations for I_hERG tails at pH 7.4 and 6.3, expressed in pA/pF, whilst in (biii) currents following each test potential were normalized to the maximum current (I_max) elicited by the protocol. (biv) The time-course of the deactivation of hERG1b-mediated current was accelerated by reduction of pH_e. The bar chart shows mean ± SEM data for the fast (τ_Fast) and slow (τ_Slow) time constant components of hERG1b deactivation measured upon repolarization to −40 mV. Addition of pH 6.3 solution did not affect τ_Fast (P = 0.7469; paired t-test), but significantly accelerated τ_slow (P = 0.0074; paired t-test).