Trifluoperazine blocks the human cardiac sodium channel, Nav1.5, independent of calmodulin.
Trifluoperazine is a phenothiazine derivative which is mainly used in the management of schizophrenia and also acts as a calmodulin inhibitor. We used the whole-cell patch-clamp technique to study the effects of trifluoperazine on human Nav1.5 (hNav1.5) currents expressed in HEK293 cells. The 50% inhibitory concentration of trifluoperazine was 15.5 ± 0.3 μM and the Hill coefficient was 2.7 ± 0.1. The effects of trifluoperazine on hNav1.5 were completely and repeatedly reversible after washout. Trifluoperazine caused depolarizing shifts in the activation and hyperpolarizing shifts in the steady-state inactivation of hNav1.5. Trifluoperazine also showed strong use-dependent inhibition of hNav1.5. The blockade of hNav1.5 currents by trifluoperazine was not affected by the whole cell dialysis of the calmodulin inhibitory peptide. Our results indicated that trifluoperazine blocks hNav1.5 current in concentration-, state- and use-dependent manners rather than via calmodulin inhibition.
College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea.
Dong-Hyun
DH
Kim
College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea.
Su-Jin
SJ
Lee
Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
Sang June
SJ
Hahn
College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea. Electronic address: jinsung.choi@catholic.ac.kr.
Jin-Sung
JS
Choi
D014150:Antipsychotic Agents / Q000737:chemistry; D002147:Calmodulin / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry; D006435:Renal Dialysis; D026941:Sodium Channel Blockers / Q000737:chemistry*; D014268:Trifluoperazine / Q000737:chemistry*
D014150:Antipsychotic Agents; D002147:Calmodulin; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010455:Peptides; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D014268:Trifluoperazine
Calmodulin inhibitor; Calmodulin inhibitory peptide; Na(v)1.5; Trifluoperazine; Voltage-gated sodium channel