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1.
Toxicol Appl Pharmacol ; 250(3): 270-7, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21059371

RESUMEN

High-voltage activated Ca(2+) (Ca(V)) channels play a key role in the regulation of numerous physiological events by causing transient changes in the intracellular Ca(2+) concentration. These channels consist of a pore-forming Ca(V)α(1) protein and three auxiliary subunits (Ca(V)ß, Ca(V)α(2)δ and Ca(V)γ). Ca(V)α(2)δ is an important component of Ca(V) channels in many tissues and of great interest as a drug target. It is well known that anticonvulsant agent gabapentin (GBP) binds to Ca(V)α(2)δ and reduces Ca(2+) currents by modulating the expression and/or function of the Ca(V)α(1) subunit. Recently, we showed that an adamantane derivative of GABA, AdGABA, has also inhibitory effects on Ca(V) channels. However, the importance of the interaction of AdGABA with the Ca(V)α(2)δ subunit has not been conclusively demonstrated and the mechanism of action of the drug has yet to be elucidated. Here, we describe studies on the mechanism of action of AdGABA. Using a combined approach of patch-clamp recordings and molecular biology we show that AdGABA inhibits Ca(2+) currents acting on Ca(V)α(2)δ only when applied chronically, both in a heterologous expression system and in dorsal root-ganglion neurons. AdGABA seems to require uptake and be acting intracellularly given that its effects are prevented by an inhibitor of the L-amino acid transport system. Interestingly, a mutation in the Ca(V)α(2)δ that abolishes GBP binding did not affect AdGABA actions, revealing that its mechanism of action is similar but not identical to that of GBP. These results indicate that AdGABA is an important Ca(V)α(2)δ ligand that regulates Ca(V) channels.


Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/fisiología , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/farmacología , Sistema de Transporte de Aminoácidos L/fisiología , Animales , Canales de Calcio/genética , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo N/fisiología , Línea Celular , Ganglios Espinales , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Mutación , Técnicas de Placa-Clamp , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/genética , Conejos , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética
2.
Chem Biol ; 13(11): 1153-60, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17113997

RESUMEN

Lymphocytes in T cell activation require extracellular nutrients to provide energy for cellular proliferation and effector functions. Therefore, inhibitors of nutrient transporters are expected to be a new class of immunosuppressant. Here, we report that the molecular target of brasilicardin A (BraA), an immunosuppressive compound, is the amino acid transporter system L. BraA inhibited the cell-cycle progression of murine T cell lymphocyte CTLL-2 cells in G1 phase, and potently inhibited the uptake of amino acids that are substrates for amino acid transport system L. Moreover, BraA stimulated the GCN2 activation and, subsequently, the phosphorylation of eIF2alpha. These results suggest that the immunosuppressive activity of BraA is induced by amino acid deprivation via the inhibition of system L and that the amino acid transporter is a target for immunosuppressant.


Asunto(s)
Sistema de Transporte de Aminoácidos L/antagonistas & inhibidores , Aminoglicósidos/farmacología , Inmunosupresores/farmacología , Aminoácidos/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones
3.
Cell Mol Neurobiol ; 22(2): 185-90, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12363200

RESUMEN

1. Although the cellular and molecular mechanisms of the anticonvulsant action of gabapentin (GBP) remain incompletely described, in vitro studies have shown that GBP binds to the alpha2delta subunit of the high voltage-activated (HVA) Ca2+ channels. 2. In this report, we analyzed the effects of GBP on the functional expression of HVA Ca2+ channels in the PC12 cell line model system. Negligible inhibition of Ca2+ channel activity was observed after acute treatment, but a significant decrease in Ca2+ current amplitude was promoted by chronic exposure to GBP. 3. Consistent with this, radioligand binding experiments showed a comparable reduction in the total number of membrane HVA N-type channels after GBP treatment.


Asunto(s)
Acetatos/farmacología , Aminas , Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Canales de Calcio Tipo N/efectos de los fármacos , Ácidos Ciclohexanocarboxílicos , Regulación hacia Abajo/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Neuronas/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Sistema de Transporte de Aminoácidos L/efectos de los fármacos , Sistema de Transporte de Aminoácidos L/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Calcio/metabolismo , Canales de Calcio Tipo N/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Regulación hacia Abajo/fisiología , Epilepsia/metabolismo , Epilepsia/fisiopatología , Gabapentina , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/metabolismo , Ratas , Células Tumorales Cultivadas , Ácido gamma-Aminobutírico/análogos & derivados , omega-Conotoxinas/farmacología
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