SEA-0400, a potent inhibitor of the Na+/Ca2+ exchanger, as a tool to study exchanger ionic and metabolic regulation.
The effects of a new, potent, and selective inhibitor of the Na(+)/Ca(2+) exchange, SEA-0400 (SEA), on steady-state outward (forward exchange), inward (reverse exchange), and Ca(2+)/Ca(2+) 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(+) (Na(i)(+)) + intracellular H(+) (H(i)(+)) 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, Na(i)(+) and H(i)(+), even in the continuous presence of SEA, releases inhibition, indicating that SEA facilitates the reversible attachment of the natural H(i)(+) and Na(i)(+) synergic inhibitors. On the basis of a recent model of squid Na(+)/Ca(2+) exchange regulation (DiPolo R and Beauge L. J Physiol 539: 791-803, 2002), we suggest that SEA acts on the H(i)(+) + Na(i)(+) 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 H(i)(+) + Na(i)(+) synergic inhibition.
Beaugé
Luis
L
Laboratorio de Biofísica, Instituto Venezolano de Investigaciones Médicas Mercedes y Martin Ferreira, Córdoba, Argentina.
DiPolo
Reinaldo
R
D000255:Adenosine Triphosphate / Q000502:physiology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D049832:Decapodiformes; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000502:physiology*
D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate