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Mol Brain
2025 May 08;181:41. doi: 10.1186/s13041-025-01211-z.
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Chlorpromazine directly inhibits Kv1.3 channels by facilitating the inactivation of channels.
Park SI
,
Hwang S
,
Lee Y
,
Lee HY
,
Kim S
,
Hong J
,
Jo SH
,
Choi SY
.
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Kv1.3 channels in microglia are pivotal in regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing Kv1.3 activity in mPFC microglia. However, the precise mechanism of CPZ's effect in the mPFC remains unclear, given that CPZ is known to inhibit dopamine receptors and the mPFC contains various cell types with dopamine receptors. In this study, we investigate how CPZ inhibits Kv1.3 channels using human Kv1.3 channel-expressing Xenopus laevis oocytes. CPZ directly inhibits Kv1.3 channel currents in a concentration-dependent manner. The CPZ-mediated Kv1.3 channel inhibition is not voltage-dependent, and CPZ accelerates Kv1.3 channel inactivation without significantly affecting its activation. Our findings suggest that CPZ directly blocks Kv1.3 channels without involving other ion channels or receptors, including dopamine receptors, thereby contributing to the understanding of its neuroinflammation-suppressing mechanism.
Fig. 1. Direct inhibition of Kv1.3 channel currents by CPZ. A Superimposed current traces obtained by applying a series of voltage pulses from -50 mV to + 50 mV upon exposure to 100 µM CPZ for 6 and 12 min. B–G Current–voltage relationship of peak (B, D) and steady-state Kv1.3 channel currents (C, E) in the presence of CPZ with indicated concentrations for 6 min (B, C) or 12 min (D, E). Peak currents were recorded at their peaks, whereas steady-state currents were determined at the end of depolarizing pulses. Peak and steady-state currents at + 50 mV in control conditions were normalized to 1. Concentration–response inhibition of peak and steady-state currents after 6-min (F) or 12-min (G) exposure to CPZ, elicited by a single + 50 mV pulse from a holding potential of − 60 mV (n = 4–13 oocytes per concentration). H Current traces elicited by 2-s depolarization from − 20 to + 50 mV from a holding potential of − 60 mV, with and without 100 µM CPZ exposure. I, J CPZ-induced blockade of peak (I) and steady-state (J) Kv1.3 currents at various voltages for 6 min (n = 5–7 oocytes per treatment). At each depolarizing voltage step, the currents under different CPZ concentrations were normalized to the currents recorded without CPZ exposure. K Comparison of 30 µM CPZ-induced inhibition of peak and steady-state Kv1.3 currents at various voltages for 6 min. Current inhibition (%) = 100 × (current with vehicle—current with CPZ)/current with vehicle. Values are shown as mean ± S.E.M
Fig. 2. CPZ facilitates the inactivation of Kv1.3 Channel. A–D The activation and inactivation traces were fitted by single exponential functions, and the time constants of activation and inactivation processes were estimated from traces elicited by a single 2-s + 50 mV pulse from a holding potential of − 60 mV. A Representative normalized current traces of the activation phase in the absence and presence of 30 and 100 µM CPZ for 12 min. Each current trace was normalized to its peak value. B Time-constant values of activation processes with and without 30 and 100 µM CPZ (n = 5–7). C Representative normalized current traces of the inactivation phase in the absence and presence of 30 and 100 µM CPZ for 12 min. Each current trace was normalized to its peak value. D Time-constant values of inactivation processes with and without 30 and 100 µM CPZ (n = 9–10). E Typical steady-state activation tail currents measured at − 50 mV following 100-ms depolarizing pulses from − 70 to + 50 mV with and without 100 and 300 µM CPZ. F Steady-state activation curves obtained by normalizing each tail current to the tail current at + 50 mV and fitting the data to a Boltzmann equation (n = 6–7). G Typical tail currents evoked by 200-ms depolarizing pulses to + 40 mV; 30-s preconditioning pulses from − 70 to 0 mV with and without 100 and 300 µM CPZ. H Steady-state inactivation curves obtained by normalizing each tail current to the tail current when depolarized to + 40 mV and fitting the data to a Boltzmann equation (n = 7–8). *P < 0.05. I A double-pulse protocol was employed to investigate the recovery of Kv1.3 from inactivation, both in the absence and presence of CPZ. The first pulse consisted of a 200 ms depolarizing pulse to + 40 mV from a holding potential of − 80 mV, followed by a second identical pulse after varying interpulse intervals ranging from 10 ms to 30 s at − 80 mV. Pulses were delivered at intervals of 30 s. J The solid lines represent the single exponential fits of the peak amplitudes of Kv1.3 currents as a function of the interpulse interval (n = 4–5). Values are shown as mean ± S.E.M
