The approximately 100 billion neurons in the human brain control the vast majority of what we are able to do, from our automatic motor functions to our emotional responses to our most complex cognitive faculties. To function properly, individual neurons depend upon information sent from other neurons in the form of neurotransmitters, a class of about 150 different chemicals that serve as messengers between one nerve cell and as many as 1,000 of its neighbors. When communication between nerve cells goes awry, any number of serious neurological and psychiatric disorders can quickly follow. It was a vital advance, then, when in the 1980s Rockefeller University scientist Paul Greengard revealed the first of a series of findings elucidating exactly what happens when a neurotransmitter touches base with its target neuron. For this work, Dr. Greengard shared the 2000 Nobel Prize in Physiology or Medicine.
When he began investigating the molecular mechanism behind neural synapses, Dr. Greengard’s hypothesis was that neurotransmitters might work in a way similar to hormones, which carry signals through the bloodstream to regulate development, metabolism, tissue function and mood. After discovering the presence in brain tissues of certain neurotransmitter-sensitive enzymes as well as protein kinases dependent on those enzymes, Dr. Greengard and his colleagues experimented with many different molecules they thought might play a role in the signal transduction process. Working with dopamine, which fellow 2000 Nobel laureate Arvid Carlsson had already shown is a key factor in several severe motor and cognitive deficits, they found that several of their test molecules either mimicked or challenged the ability of neurotransmitters to elicit responses in neurons. Over the next several years, Dr. Greengard tracked these individual molecular clues and mapped out the chain of biochemical events that begins with the neurotransmitter reaching a receptor on the outer membrane of the neuron.
When Dr. Greengard conclusively described the cascade of events that make up a neuron’s response to dopamine stimulation, much of the scientific community balked, but his findings soon proved accurate not only for dopamine but for many other neurotransmitters as well. Receptors on the neuron cell surface first activate enzymes in the cell wall; the enzymes then initiate the second-messenger molecule known as cyclic AMP, which travels into the cell and activates a protein kinase; finally, the protein kinase starts to phosphorylate — bind phosphate groups to — other proteins, thus activating or deactivating them. The proteins thus affected can initiate other actions, including translating DNA for the production of new proteins; increasing the number of receptors at the cell surface to heighten the neuron’s sensitivity; or opening ion channels in the cell membrane to increase the neuron’s excitability.
Because the process can take anywhere from hundreds of milliseconds to minutes to complete, it is known as slow synaptic transmission. Fast-acting neurotransmitters, in contrast, complete their task in under one millisecond. Dr. Greengard showed that not only is slow synaptic transmission the more common type of signal transduction, but several fast-acting pathways are modulated by slow-synaptic processes. Fast- and slow-synaptic transmission, he concluded, are respectively analogous to the hardware of a computer and the software that controls it.
Dr. Greengard also discovered DARPP-32 (dopamine and cyclic AMP regulated phosphoprotein, of molecular weight 32 kDa), a central regulatory protein that mediates the action of dopamine by acting like an air traffic controller, guiding other proteins in when and how to be activated. At least a dozen neurotransmitters have been shown to use DARPP-32. It is, furthermore, the first demonstrated example of a molecule that can act as either a protein kinase (which phosphorylates) or a phosphatase inhibitor.
Dysfunctions in dopaminergic pathways have been directly implicated in the pathogenesis of numerous neurological and psychiatric disorders. Dr. Greengard’s work has established many of these causative connections and has led to the development of dopamine-targeted treatments for Parkinson’s disease, schizophrenia and attention deficit/hyperactivity disorder. It has also provided insight into the brain’s response to numerous addictive substances, including amphetamine, caffeine, cocaine, ethanol, LSD, morphine, nicotine and PCP. Dr. Greengard shared the 2000 prize with Arvid Carlsson of Göteborg University and Eric Kandel of Columbia University.
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. In addition to the Nobel Prize, his recent awards include the Karolinska Institute’s Gold Medal and the Dart/NYU Biotechnology Achievement Award both in 2010.