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

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-depend...

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Published in:Molecular pharmacology 2004-03, Vol.65 (3), p.802-810
Main Authors: Bouchard, Ron, Omelchenko, Alexander, Le, Hoa Dinh, Choptiany, Platon, Matsuda, Toshio, Baba, Akemichi, Takahashi, Kenzo, Nicoll, Debora A., Philipson, Kenneth D., Hnatowich, Mark, Hryshko, Larry V.
Format: Article
Language:English
Subjects:
Aniline Compounds - pharmacology
Animals
Calcium - metabolism
Electrophysiology
Oocytes - drug effects
Oocytes - metabolism
Oocytes - physiology
Phenyl Ethers - pharmacology
Sodium - metabolism
Sodium-Calcium Exchanger - antagonists & inhibitors
Sodium-Calcium Exchanger - metabolism
Xenopus laevis
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.65.3.802