RT Journal Article
SR Electronic
T1 Effects of SEA0400 on Mutant NCX1.1 Na<sup>+</sup>-Ca<sup>2+</sup> Exchangers with Altered Ionic Regulation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 802
OP 810
DO 10.1124/mol.65.3.802
VO 65
IS 3
A1 Ron Bouchard
A1 Alexander Omelchenko
A1 Hoa Dinh Le
A1 Platon Choptiany
A1 Toshio Matsuda
A1 Akemichi Baba
A1 Kenzo Takahashi
A1 Debora A. Nicoll
A1 Kenneth D. Philipson
A1 Mark Hnatowich
A1 Larry V. Hryshko
YR 2004
UL http://molpharm.aspetjournals.org/content/65/3/802.abstract
AB 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.