Solomon H. Snyder, M.D.
Information processing in the brain reflects communication among neurons via neurotransmitters. The major chemical classes of neurotransmitters are biogenic amines, amino acids and peptides. During the past few years we have identified and characterized novel transmitters or neuromodulators which overturn much dogma in the field. For instance, we discovered that nitric oxide (NO) satisfies the major criteria of a neurotransmitter, as NO synthase is localized to specific neuronal populations and inhibitors of the enzyme block neurotransmission in certain systems. Yet NO is a gas which cannot be stored in synaptic vesicles, released by exocytosis, or act at receptor proteins on cell membranes. In vascular stroke excess release of the excitatory amino acid neurotransmitter glutamate activates NO synthase to form NO that mediates neurotoxicity. Evidence for this includes the blockade of stroke damage by inhibitors of NO synthase and a lesser amount of stroke damage in the brains of mice lacking the neuronal form of NO synthase. In mice in which the gene for the neuronal NO synthase has been “knocked out” we observe dramatic alterations in social and sexual behavior indicating a prominent role for NO in aggression and sexual attraction.
At least one other gas, carbon monoxide (CO) may be a neurotransmitter. CO is formed by the action of the enzyme heme oxygenase, which cleaves the heme ring liberating CO and forming biliverdin, which is converted to bilirubin. We found that a neuronal form of heme oxygenase occurs in discrete neuronal populations in the brain, and CO formed from it may be involved in regulating levels of cyclic GMP. Just as NO, formed in the endothelial layer of blood vessels, diffuses to the smooth muscle and is a major normal relaxing element of blood vessels, CO is formed by heme oxygenase in the endothelium and also relaxes blood vessels.
D-Serine may be a neurotransmitter, as improbable as the gases, being the “wrong” isomer and occurring in glia, not neurons. Levels of D-serine in the brain are a third those of L-serine, and it is the only D-amino acid to occur in substantial levels in the brain. Our immunohistochemical maps reveal D-serine in a unique population of glia, protoplasmic astrocytes, which ensheathe nerve terminals selectively in regions of the brain enriched in the subtype of gluatamate receptor referred to as the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors had been thought to be co-activated by the amino acids glycine and glutamate. D-Serine appears to be the normal stimulus for the glycine site of this receptor. D-Serine is released from these astrocytes by glutamate acting at an AMPA subtype of receptor. We gave cloned serine yaccmase, which L-to D-serine.
- Sabatini, D.M., Barrow, R.K., Blackshaw, S., Burnett, P.E., Lai, M.M., Field, M.E., Bahr, B.A., Kirsch, J., Betz, H., and Snyder, S.H., Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling, Science, 284: 1161-1164, 1999.
- Ferris, C.D., Jaffrey, S.R., Sawa, A., Takahashi, M., Brady, S.D., Barrow, K.K., Tysoe, S.A., Wolosker, H., Baranano, D.E., Dore, S., Poss, K.D., and Snyder, S.H., Haem oxygenase-1 prevents cell death by regulating cellular iron, Nature Cell Biology, 1: 152-157, 1999.
- Wolosker, H., Blackshaw, S., and Snyder, S.H., Serine racemase: A glial enzyme Synthesizing D-serine to regulate glutamate-N-methyl-D aspartate neurotransmission, PNAS, 96: 13409-13414, 1999.
- Ha, H. C., and Snyder, S.H., Poly(ADP-ribose) polymerase-1 in the nervous system, Neurobiology of Disease, 7: 225-239, 2000.