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SEA-0400, a potent inhibitor of the Na+/Ca2+ exchanger, as a tool to study exchanger ionic and metabolic regulation
Authors:Beaugé Luis  DiPolo Reinaldo
Institution:Laboratorio de Biofísica, Instituto Venezolano de Investigaciones Médicas Mercedes y Martin Ferreira, Córdoba, Argentina.
Abstract:The effects of a new, potent, and selective inhibitor of the Na+/Ca2+ exchange, SEA-0400 (SEA), on steady-state outward (forward exchange), inward (reverse exchange), and Ca2+/Ca2+ transport exchange modes were studied in internally dialyzed squid giant axons from both the extra- and intracellular sides. Inhibition by SEA takes place preferentially from the intracellular side of the membrane. Its inhibition has the following characteristics: it increases synergic intracellular Na+ (Nai+) + intracellular H+ (Hi+) inactivation, is antagonized by ATP and intracellular alkalinization, and is enhanced by intracellular acidification even in the absence of Na+. Inhibition by SEA is still present even after 1 h of its removal from the experimental solutions, whereas removal of the cointeracting agents of inhibition, Nai+ and Hi+, even in the continuous presence of SEA, releases inhibition, indicating that SEA facilitates the reversible attachment of the natural Hi+ and Nai+ synergic inhibitors. On the basis of a recent model of squid Na+/Ca2+ exchange regulation (DiPolo R and Beaugé L. J Physiol 539: 791–803, 2002), we suggest that SEA acts on the Hi+ + Nai+ inactivation process and can interact with the Na+-free and Na+-bound protonized carrier. Protection by ATP concurs with the antagonism of the nucleotide by Hi+ + Nai+ synergic inhibition. ionic-metabolic interactions
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