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Molecular Pharmacology

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Research ArticleArticle

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

Ron Bouchard, Alexander Omelchenko, Hoa Dinh Le, Platon Choptiany, Toshio Matsuda, Akemichi Baba, Kenzo Takahashi, Debora A. Nicoll, Kenneth D. Philipson, Mark Hnatowich and Larry V. Hryshko
Molecular Pharmacology March 2004, 65 (3) 802-810; DOI: https://doi.org/10.1124/mol.65.3.802
Ron Bouchard
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Alexander Omelchenko
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Hoa Dinh Le
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Platon Choptiany
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Toshio Matsuda
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Akemichi Baba
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Kenzo Takahashi
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Debora A. Nicoll
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Kenneth D. Philipson
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Mark Hnatowich
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Larry V. Hryshko
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Abstract

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.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (3)
Molecular Pharmacology
Vol. 65, Issue 3
1 Mar 2004
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Research ArticleArticle

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

Ron Bouchard, Alexander Omelchenko, Hoa Dinh Le, Platon Choptiany, Toshio Matsuda, Akemichi Baba, Kenzo Takahashi, Debora A. Nicoll, Kenneth D. Philipson, Mark Hnatowich and Larry V. Hryshko
Molecular Pharmacology March 1, 2004, 65 (3) 802-810; DOI: https://doi.org/10.1124/mol.65.3.802

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Research ArticleArticle

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

Ron Bouchard, Alexander Omelchenko, Hoa Dinh Le, Platon Choptiany, Toshio Matsuda, Akemichi Baba, Kenzo Takahashi, Debora A. Nicoll, Kenneth D. Philipson, Mark Hnatowich and Larry V. Hryshko
Molecular Pharmacology March 1, 2004, 65 (3) 802-810; DOI: https://doi.org/10.1124/mol.65.3.802
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