Mechanism of hydrogen sulphide-mediated signaling cascade through N-methyl-D-aspartate receptors

Abstract

Employing cultured murine primary cortical neurons, hydrogen sulphide (H2S) is demonstrated to aggravate glutamate-induced neuronal death, and alone is able to induce cytotoxicity in a dose- and time-dependent manner via activation of calcium-dependent proteases, calpains. Application of specific glutamate receptor pharmacological inhibitors further revealed that H2S-activated neuronal death signaling cascade revolving around N-methyl-D-aspartate (NMDA) and kainate receptors. Microarray analysis of H2S-treated samples at (5h, 15h and 24h) showed 6, 780 genes with significant regulation of 1.5 fold-change. Among them included genes related to apoptosis, endoplasmic reticulum stress, calcium homeostasis, cell survival and cycle, heat shock proteins and chaperones, ubiquitin proteasome system (UPS), ionic and water channels. Comparison between H2S- and NMDA-mediated neuronal deaths revealed involvement of identical signaling cascades, though the former initiated at a later time-point (15 h) than the latter (5 h).