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 β-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.