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Br J Pharmacol. 2015 Nov;172(21):5161-73. doi: 10.1111/bph.13283. Epub 2015 Oct 9.

State-dependent blocking mechanism of Kv 1.3 channels by the antimycobacterial drug clofazimine.

Author information

1
Laboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center, Honolulu, HI, 96813, USA.
2
John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96813, USA.

Abstract

BACKGROUND AND PURPOSE:

Kv 1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca(2+) signalling in T cells by regulating the membrane potential and with it the driving force for Ca(2+) influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen-induced Ca(2+) oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv 1.3 channels with high potency and selectivity.

EXPERIMENTAL APPROACH:

We used patch-clamp methodology to investigate clofazimine's mechanism of action in Kv 1.3 channels expressed in HEK293 cells.

KEY RESULTS:

Clofazimine blocked Kv 1.3 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. Kv 1.3 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 Kv 1.3 in shaping Ca(2+) oscillations, the use-dependent and state-dependent block of Kv 1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which Kv 1.3-expressing T cells play a significant role.

PMID:
26276903
PMCID:
PMC4687807
DOI:
10.1111/bph.13283
[Indexed for MEDLINE]
Free PMC Article

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