Effects of Estradiol and IGF-1 on the Sodium Calcium Exchanger in Rat Cultured Cortical Neurons
The Na+/Ca2+ exchanger (NCX) is an important bidirectional transporter of calcium in neurons and has been shown to be involved in neuroprotection. Calcium can activate a number of cascades that can result in apoptosis and cell death, and NCX is a key factor in regulating the cytoplasmic concentration of this ion. 17-β-estradiol and insulin-like growth factor 1 (IGF-1) are known neuroprotective hormones with interacting mechanisms and effects on intracellular calcium; however, their relationship with the NCX has not been explored. In this article, the effects of these two hormones on neuronal NCX were tested using the whole-cell patch clamp technique on rat primary culture neurons. Both 17-β-estradiol and IGF-1 produced an increase in the NCX-mediated inward current and a decrease in the NCX-mediated outward current. However, the IGF-1 effect was lower than that of 17-β-estradiol, and the effect of both agents together was greater than the sum of each agent alone. Neither of the agents affected the pattern of regulation by extracellular or intrapipette calcium. Inhibitors of the IGF-1 and 17-β-estradiol receptors and inhibitors of the main signaling pathways failed to change the observed effects, indicating that these actions were not mediated by the classical receptors of these hormones. These effects on the NCX could be a mechanism explaining the neuroprotective actions of 17-β-estradiol and IGF-1, and these findings could help researchers to understand the role of the NCX in neuroprotection.
KeywordsNCX Estradiol IGF-I Electrophysiology Neuroprotection
We thank to the Red de Universidades Públicas del Eje Cafetero Alma Máter and Colciencias for financial support.
- Amoroso S, Tortiglione A, Secondo A, Catalano A, Montagnani S, Di Renzo G, Annunziato L (2000) Sodium nitroprusside prevents chemical hypoxia-induced cell death through iron ions stimulating the activity of the Na+–Ca2+ exchanger in C6 glioma cells. J Neurochem 74:1505–1513PubMedCrossRefGoogle Scholar
- Araujo IM, Carreira BP, Pereira T, Santos PF, Soulet D, Inacio A, Bahr BA, Carvalho AP, Ambrosio AF, Carvalho CM (2007) Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons. Cell Death Differ 14:1635–1646PubMedCrossRefGoogle Scholar
- Busa W (1996) Regulation of intracellular free calcium. In: Shultz S, Andreoli T, Brown A, Frambrough D, Hoffman J, Welsh M (eds) Molecular biology of membrane transport disorders. Plenum Press, New York, pp 427–446Google Scholar
- Gonthier B, Nasarne C, Rudiger T (2005). Protocol for the primary culture of cortical neurons. In: Poindron P (ed) New methods for culturing cells from nervous tissue. Bio Valley Monographs, Karger, Basel, pp 12–22Google Scholar
- Pignataro G, Gala R, Cuomo O, Tortiglione A, Giaccio L, Castaldo P, Sirabella R, Matrone C, Canitano A, Amoroso S, Di Renzo G, Annunziato L (2004a) Two sodium/calcium exchanger gene products, NCX1 and NCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke 35:2566–2570PubMedCrossRefGoogle Scholar
- Pignataro G, Tortiglione A, Scorziello A, Giaccio L, Secondo A, Severino B, Santagada V, Caliendo G, Amoroso S, Di Renzo G, Annunziato L (2004b) Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats. Neuropharmacology 46:439–448PubMedCrossRefGoogle Scholar
- Tortiglione A, Pignataro G, Minale M, Secondo A, Scorziello A, Di Renzo GF, Amoroso S, Caliendo G, Santagada V, Annunziato L (2002) Na+/Ca2+ exchanger in Na+ efflux-Ca2+ influx mode of operation exerts a neuroprotective role in cellular models of in vitro anoxia and in vivo cerebral ischemia. Ann N Y Acad Sci 976:408–412PubMedCrossRefGoogle Scholar