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Solomon H. Snyder

Solomon H. Snyder

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.  

Snyder Figure
Diagram of Nitric Oxide (NO) and carbon monoxide (CO) disposition at synapses. These two substances have been characterized in our laboratory as atypical neurotransmitters. As gases, they cannot be stored in synaptic vesicles, released by exocytosis or bind to receptor proteins on the external surface of neurons. They are formed "on demand" by activation of their biosynthetic enzymes. Neuronal depolarization leads to calcium influx that binds to calmodulin, stimulating NO synthase as well as heme oxygenase-9. Both NO and CO diffuse into adjacent cells to activate guanylyl cyclase to form cyclic GMP. Additionally, NO S-nitrosylates a wide range of proteins. 

Representative Publications:

  • Snyder, S.H.  Mind Molecules. J Biol Chem.  2011 Jun 17; 286(24):21023-32. Epub 2011 May 4.  Pub Med Reference
  • Kornberg, M.D., Sen, N., Hara, M.R., Juluri, K.R., Nguyen, J.V., Snowman, A.M., Law, L., Hester, L.D., Snyder, S.H. GAPDH mediates nitrosylation of nuclear proteins.  Nat Cell Biol. 2010 Nov; 12(11):1094-100.  Pub Med Reference
  • Mustafa, A.K., Gadalla, M.M., Sen, N., Kim, S., Mu, W., Gazi, S.K., Barrow, R.K., Yang, G., Wang, R., Snyder, S.H. H2S signals through protein S-sulfhydration.  Sci Signal. 2009 Nov 10; 2(96):ra72. Pub Med Reference
  • Subramaniam, S., Sixt, K.M., Barrow, R., Snyder, S.H.  Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity.  Science. 2009 Jun 5; 324(5932):1327-30. Pub Med Reference

  • Yang, G., Wu, L., Jiang, B., Yang, W., Qi, J., Cao, K., Meng, Q., Mustafa, A.K., Mu, W., Zhang, S., Snyder, S.H., Wang, R.  H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.  Science. 2008 Oct 24; 322(5901):587-90.  Pub Med Reference
  • van Rossum, D.B., Patterson, R.L., Sharma, S., Barrow, R.K., Kornberg, M., Gill, D.L., Snyder, S.H.  Phospholipase Cg1 controls surface expression of TRPC3 through an intermolecular PH domain.  Nature. 2005 March 3; 434:99-104.  Pub Med Reference
  • Kim SF, Huri, D.A., Snyder, S.H. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2.  Science. 2005 Dec 23; 310(5756):1966-70.  Pub Med Reference
  • Hara, M.R., Agrawal, N., Kim, S.F., Cascio, M.B., Fujimuro, M., Ozeki, Y., Takahashi, M., Cheah, J.H., Tankou, S.K., Hester, L.D., Ferris, C.D., Hayward, S.D., Snyder, S.H., Sawa A.  S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.  Nat Cell Biol. 2005 Jul; 7(7):665-74.  Pub Med Reference
  • Saiardi, A., Bhandari, R., Resnick, A.C., Snowman, A.M., Snyder, S.H. Phosphorylation of proteins by inositol pyrophosphates.  Science. 2004 Dec 17; 306(5704): 2101-5. Pub Med Reference
  • Chakraborty, A., Koldobskiy, M.A., Bello, N.T., Maxwell, M., Potter, J.J., Juluri, K.R., Maag, D., Kim, S., Huang, A.S., Dailey, M.J., Saleh, M., Snowman, A.M., Moran, T.H., Mezey, E., Snyder, S.H. Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell. 2010 Dec 10; 143(6):897-910. Pub Med Reference

Other graduate programs in which Dr. Snyder participates:

BCMB Program
Cellular and Molecular Medicine Graduate Program

Neuroscience Graduate Program

 
 
 
 
 
 

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