Dr. Greengard and his colleagues have shown that nerve cells communicate with each other through two mechanisms: fast and slow synaptic transmission. Fast-acting neurotransmitters, including glutamate (which is excitatory) and GABA (which is inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amines and peptide neurotransmitters, as well as some of the effects of the fast-acting neurotransmitters, are achieved over hundreds of milliseconds to minutes by slow synaptic transmission, which is mediated through an enormously more complicated sequence of biochemical steps. Researchers in the laboratory use a multidisciplinary approach to study neuronal function and signal integration.

The Greengard lab is elucidating the signal transduction pathways through which dopamine and other neurotransmitters elicit physiological effects on their target neurons in the basal ganglia: At least a dozen neurotransmitters that regulate the activity of these neurons do so in large measure by regulating the phosphorylation of a pivotal signaling switch called DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein, Mr32kDA). DARPP-32 is the first known example of a molecule that can act either as a protein kinase or phosphatase inhibitor.

The lab has clarified much of the signaling machinery involved in the action of dopamine and other neurotransmitters that interact with the dopamine pathway, elucidated new principles of signal transduction and identified new targets for the development of drugs to treat several major psychiatric and neurological disorders. DARPP-32 provides a molecular mechanism by which all efferent information from the striatum is integrated and converted into a meaningful physiological response. Dr. Greengard’s research indicates that the essential role of DARPP-32 in cell signaling in the brain extends far beyond the dopamine signaling system and appears to involve a large number of neurotransmitters in many brain regions.

The Greengard lab demonstrated that protein phosphorylation and dephosphorylation mechanisms control the relative amounts of Alzheimer amyloid precursor protein (APP) converted to the nontoxic soluble form of APP and the toxic amyloid- (). Activators of various protein kinases, as well as inhibitors of various protein phosphatases, reduce the amount of formed by nerve cells. Work is now under way in the lab to determine the components of the signal transduction cascade responsible for the regulation of APP breakdown and the formation of A, with the aim of developing new targets for the treatment of Alzheimer’s disease. Dr. Greengard and his colleagues identified the protein p11 as a regulator of serotonin signaling in the brain. They have shown that p11 increases the concentration of the serotonin 1B receptor (5HT1B) at synapses, thereby increasing the efficiency of serotonin signaling. The interaction between p11 and 5HT1B appears to play a key role in regulating an individual’s susceptibility to depression and response to antidepressant treatments.

Other research from Dr. Greengard’s lab provides evidence for an essential role of genome-encoded microRNAs in survival of differentiated neurons. Conditional Purkinje cell-specific ablation of the key microRNA-generating enzyme Dicer leads to Purkinje cell death. Deficiency in Dicer is associated with progressive loss of microRNAs followed by cerebellar degeneration and development of ataxia. This pattern of Purkinje cell degeneration in the absence of microRNAs bears obvious similarity to processes associated with such slow-progressing neurodegenerative diseases as Alzheimer’s and Parkinson’s.

CAREER

Dr. Greengard received his Ph.D. in biophysics from The Johns Hopkins University in 1953. Before joining Rockefeller in 1983 as a Vincent Astor Professor and head of laboratory, he was director of biochemical research at the Geigy Research Laboratories and a professor of pharmacology at Yale University. Since 1995 he has directed the Fisher Center for Alzheimer’s Disease Research at Rockefeller.

Dr. Greengard is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. Among his many awards and honors are the 2000 Nobel Prize in Physiology or Medicine, the 1998 New York City Mayor’s Award for Excellence in Science and Technology and the 1997 Charles A. Dana Award for Pioneering Achievements in Health.