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Effects of SEA0400 on Mutant NCX1.1 Na⁺-Ca²⁺ Exchangers with Altered Ionic Regulation

Institute of Cardiovascular Sciences, University of Manitoba, Faculty of Medicine, St. Boniface Research Centre, Winnipeg, Manitoba, Canada (R.B., A.O., H.D.L., P.C., M.H., L.V.H.); Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (T.M., A.B.,); Taisho Pharmaceutical Co., Ltd., Tokyo, Japan (K.T.); and UCLA Cardiovascular Research Labs, Los Angeles, California (D.A.N., K.D.P.)

SEA0400 (SEA) blocks cardiac and neuronal Na⁺-Ca²⁺ exchange with the highest affinity of any known inhibitor, yet very little is known about its molecular mechanism of action. Previous data from our lab suggested that SEA stabilizes or modulates the transition of NCX1.1 exchangers into a Na⁺_i-dependent (I₁) inactive state. To test this hypothesis, we examined the effects of SEA on mutant exchangers with altered ionic regulatory properties. With mutants where Na⁺_i-dependent inactivation is absent, the effects of SEA were greatly reduced. Conversely, with mutants displaying accelerated Na⁺_i-dependent inactivation, block of NCX1.1 by SEA was either enhanced or unchanged, depending upon the phenotype of the particular mutation. With mutant exchangers where Ca²⁺_i-dependent (I₂) inactivation was suppressed, block of exchange currents by SEA was similar to that observed for wild-type NCX1.1. These data strongly support the involvement of I₁ inactivation in the inhibitory mechanism of NCX1.1 by SEA, whereas I₂ inactivation does not seem to serve an important role. The involvement of processes regulated by intracellular Na⁺ in the inhibitory mechanism of SEA may prove to be particularly important when considering the potential cardioprotective effects of this agent.

Received August 25, 2003; accepted November 26, 2003.

Address correspondence to: Dr. Larry V. Hryshko, Institute of Cardiovascular Sciences, University of Manitoba Faculty of Medicine, St. Boniface Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, Canada, R2H 2A6. E-mail: lhryshko{at}sbrc.ca

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