Fig. 3: Effect of JNJ-67869386 and JNJ-799760 on the kinetics of closed-state desensitization. | Communications Biology

Fig. 3: Effect of JNJ-67869386 and JNJ-799760 on the kinetics of closed-state desensitization.

From: Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

Fig. 3

a and b Current traces showing the time course of development of pH 7.1-induced desensitization without (a) or with (b) 100 nM JNJ-67869386. Brief pH 6.0 test pulses (thin vertical bars above the current traces) are applied immediately before and at various times during the pH 7.1 application. Inter-pulse interval = 120 s (a) and 150 s (b). c Summary of all experiments like (a) and (b). Data are normalized to the first pH 6.0 (pre-pH 7.1) peak and fitted to a single exponential function with time constants of 2.9 ± 0.1 s (control; n = 6) and 15.1 ± 1.3 s (JNJ-67869386; n = 6), respectively. The JNJ-67869386 data are statistically different from control (p < 0.001; Two-way ANOVA). d and e Current traces showing the time course of recovery from pH 7.1-induced desensitization without (d) or with (e) 100 nM JNJ-67869386. A 60/100 s (control/JNJ-67869386) pH 7.1 pulse is preceded by a brief pH 6.0 pulse and followed by a pH 8.2 pulse interspersed with brief pH 6.0 pulses (thin vertical bars above the current traces) at various intervals. f Summary of all experiments like (d) and (e). Data are normalized to the first pH 6.0 (pre-pH 7.1) peak and fitted to a single (control/30 µM amiloride) or double (100 nM JNJ-67869386/JNJ-799760) exponential function with time constants of 231.5 ± 17.4 ms (control; n = 6), 277.6 ± 35.9 ms (amiloride; n = 4), 381.0 ± 85.1 ms/1.4 ± 0.4 s (JNJ-67869386; n = 6) and 400.0 ms/1.0 ± 0.4 s (JNJ-799760; n = 6), respectively. Data for JNJ-67869386 and JNJ-799760 (p < 0.001 for both), but not amiloride (p > 0.5), are statistically different from control (two-way ANOVA).

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