Department Affiliation: Primary: Neuroscience; Secondary: Pharmacology and Molecular Sciences; Psychiatry
Degree: M.D., Georgetown
Rank: Professor
Telephone Number: 410-955-3024
Fax Number: 410-955-3623
E-mail address: ssnyder@jhmi.edu
School of Medicine Address: 813 Wood Basic Science Building, 725 N. Wolfe St., Baltimore, MD 21205
Neurotransmitters, second messengers and drug action in the nervous system
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. Besides forming CO, heme oxygenase action gives rise to ferrous iron and biliverdin which is rapidly reduced to bilirubin. We have shown that bilirubin is a key neuronal antioxidant neuroprotectant. Low nanomolar concentrations of bilirubin reverse the oxidant effects of 10,000 times higher concentrations of oxidants, an amplification mediated by a unique bilverdin reductase cycle. When bilirubin acts as an antioxidant, it is oxidized to biliverdin. Biliverdin reductase rapidly reforms bilirubin. Deletion of biliverdin reductase from cells leads to excess oxidation and cell death.
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, which ensheathe nerve terminals selectively in regions of the brain enriched in the subtype of glutamate 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 the AMPA subtype of receptor. Selective destruction of D-serine by D-amino acid oxidase markedly reduces NMDA neurotransmission. A novel enzyme, serine racemase, transforms L- to D-serine. It binds to GRIP, a scaffolding protein that links serine racemase to AMPA receptors so that glutamate transmission markedly activate the enzyme with associated release of D-serine.
Representative Publications:
- Boehning D, Snyder SH. Novel neural modulators. Annu Rev Neurosci. 2003;26:105-31. Pub Med Reference
- Saiardi A, Bhandari R, Resnick AC, Snowman AM, Snyder SH. Phosphorylation of proteins by inositol pyrophosphates. Science. 2004 Dec 17;306(5704):2101-5. Pub Med Reference
- Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005 Dec 23;310(5756):1966-70. Pub Med Reference
- Bhandari R, Saiardi A, Ahmadibeni Y, Snowman AM, Resnick AC, Kristiansen TZ, Molina H, Pandey A, Werner JK Jr, Juluri KR, Xu Y, Prestwich GD, Parang K, Snyder SH. Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event. Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15305-10. Pub Med Reference
- Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3456-9. Pub Med Reference
- Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N, Thomas B, Dawson TM, Dawson VL, Snyder SH, Sawa A. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008 Jul;10(7):866-73. PMCID: PMC2689382 Pub Med Reference
- Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008 Oct 24;322(5901):587-90. NIHMSID # 121068. Pub Med Reference
- Mustafa AK, Gadalla MM, Snyder SH. Signaling by gasotransmitters. Sci Signal. 2009 Apr 28;2(68). NIHMSID # 126255 Pub Med Reference
Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science. 2009 Jun 5;324(5932):1327-30. NIHMSID # 126261 Pub Med Reference
Other graduate programs in which Dr. Snyder participates:
