Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor

Hydrogen sulfide (H(2)S) is produced endogenously from l-cysteine in mammalian tissues, and may function as a neuromodulator in the brain as well as a tone regulator in smooth muscle. H(2)S is present at relatively high levels in the brain, and cystathionine beta-synthase (CBS), which is highly expressed in the hippocampus, is involved in the production of brain H(2)S. Physiological concentrations of H(2)S selectively enhance NMDA receptor-mediated currents and facilitate the induction of hippocampal long-term potentiation (LTP). The NMDA receptor subunits are directly phosphorylated at specific sites by protein kinase A (PKA), resulting in the activation of NMDA-receptor-mediated excitatory postsynaptic currents. PKA activation is also observed in the induction of LTP. Here we show that physiological concentrations of H(2)S increase the production of cAMP in primary cultures of brain cells, neuronal and glial cell lines, and Xenopus oocytes. NMDA receptors expressed on Xenopus oocyte membrane are modulated by H(2)S. This modulation by H(2)S is specifically inhibited by adenylyl cyclase-specific inhibitor MDL-12, 330A. The present findings provide a mechanism for the previous observation that H(2)S modulates NMDA receptors and enhances the induction of LTP.