Phenylarsine oxide increases intracellular calcium mobility and inhibits Ca2+-dependent ATPase activity in thymocytes
1999
Hmadcha, Abdelkrim | Carballo Álvarez, Modesto | Conde, Manuel | Márquez, Gracia | Monteseirín Mateo, Javier | Martín-Nieto, José | Bedoya Bergua, Francisco Javier | Pintado Sanjuan, Elizabeth | Sobrino Beneyto, Francisco | Martín-Nieto, José | Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología | Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular | Hospital Universitario Virgen Macarena. Servicio de Inmunología y Alergia | Genética Humana y de Mamíferos
A rise in intracellular Ca2+ levels has been implicated as a regulatory signal for the initiation of lymphocyte proliferation. In the present study the mechanism underlying the elevation of [Ca2+] induced by phenylarsine oxide [PAO] was investigated in thymocytes. This agent inhibits HIV-1 replication and also NF-κB-mediated activation. It has been reported that the PAO-induced Ca2+ elevation results from an enhanced plasma membrane calcium permeability in T cells. Here, we present biochemical evidence that the PAO-induced Ca2+ increase was independent of external Ca2+. Consistent with these facts, when [Ca2+]i was depleted by prolonged incubation of the cells in Ca2+-free medium, PAO addition did not lead to [Ca2+]i increase. These data indicate the involvement of intracellular organelles of thymocytes as the source of Ca2+. Moreover, evidence is presented that PAO inhibited Ca2+-dependent ATPase activity from thymocytes and sarcoplasmic reticulum from skeletal muscle. This inhibition was dose-dependent, with a IC50 of about 30 μM for both preparations of enzyme. The ability of PAO to inhibit Ca2+-dependent ATPase represents a novel mechanism of action for this drug. Present data suggest that the PAO-dependent [Ca2+]i increase could be mainly the result of inhibition of Ca2+-dependent ATPase. In addition, we describe also a Ca2+-dependence for PAO effect on tyrosine phosphorylation.
Show more [+] Less [-]This work was supported by grants from Fondo Investigaciones Sanitarias (FIS) of Spain (94/1484 and 97/1289), grants from Junta de Andalucía (Consejería de Salud) given to F.S. (200/98) and E.P. (84/98), and the Fundation of SEAIC of Spain, given to J.M. G.M. is a recipient of a fellowships from FIS.
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