State‐dependent blocking mechanism of K_v1.3 channels by the antimycobacterial drug clofazimine

Background and Purpose

K_v1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca²⁺ signalling in T cells by regulating the membrane potential and with it the driving force for Ca²⁺ influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen‐induced Ca²⁺ oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting K_v1.3 channels with high potency and selectivity.

Experimental Approach

We used patch‐clamp methodology to investigate clofazimine's mechanism of action in K_v1.3 channels expressed in HEK293 cells.

Key Results

Clofazimine blocked K_v1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use‐dependent open‐channel block during long depolarizations, resulting in accelerated K⁺ current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use‐dependent and state‐dependent in that they clearly required prior channel opening. The clofazimine‐sensitive closed‐deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C‐type inactivated state significantly affected. K_v1.3 channels carrying the H399T mutation and lacking C‐type inactivation were insensitive to clofazimine block of the closed‐deactivated state, but retained their susceptibility to open‐channel block.

Conclusions and Implications

Given the prominent role of K_v1.3 in shaping Ca²⁺ oscillations, the use‐dependent and state‐dependent block of K_v1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which K_v1.3‐expressing T cells play a significant role.

DOI: 10.1111/bph.13283

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