Paul Greengard was an American neuroscientist whose research transformed the understanding of brain function. He is recognized for his discoveries concerning neurotransmitters and signal transduction within the nervous system. This work earned him the Nobel Prize in Physiology or Medicine in 2000, establishing a new paradigm for brain communication at a molecular level.
Early Life and Formative Years
Paul Greengard was born on December 11, 1925, in New York City. His mother passed away during his birth, and he was subsequently raised in a Christian tradition by his stepmother. During World War II, Greengard served in the United States Navy as an electronics technician, where he contributed to the development of early warning systems at the Massachusetts Institute of Technology.
After the war, he attended Hamilton College, graduating in 1948 with a degree in mathematics and physics. He chose not to pursue graduate studies in theoretical physics due to the field’s focus on nuclear weapons research at the time. Instead, he developed an interest in biophysics, leading him to Johns Hopkins University where he earned his Ph.D. in 1953. Following his doctoral work, Greengard conducted postdoctoral studies for five years across various institutions in England and Amsterdam, including the University of London, Cambridge University, and the National Institute for Medical Research.
Unlocking Brain Communication: The Nobel-Winning Discovery
In the late 1960s, neurotransmitters like dopamine, noradrenaline, and serotonin were known to exist, but their precise mechanisms of action were unclear. Paul Greengard’s research shifted the focus from electrical aspects of neural signaling to underlying biochemical processes. He explored the chemical basis of neuronal communication.
Greengard demonstrated that neurotransmitters influence nerve cell function through slow synaptic transmission. This mechanism involves protein phosphorylation, a chemical reaction where a phosphate molecule attaches to a protein, altering its shape and function. When a neurotransmitter, such as dopamine, binds to a receptor on a neuron’s outer membrane, it triggers a cascade of events.
This binding increases cyclic AMP (cAMP) inside the cell. Elevated cAMP then activates protein kinase A, which adds phosphate groups to other proteins within the nerve cell. This phosphorylation changes the neuron’s activity. Greengard also identified DARPP-32, a central regulatory protein that mediates dopamine’s effects and acts as a molecular switch, influencing other proteins and affecting fast synaptic transmission.
Beyond the Nobel: Other Key Research Areas
Following his work on slow synaptic transmission, Paul Greengard expanded his research to investigate how disruptions in these signaling pathways contribute to various brain disorders. His investigations also delved into the molecular basis of how therapeutic drugs exert their effects in the brain.
His laboratory found protein kinase A highly concentrated in the brain, identifying specific target proteins for this enzyme. He also isolated protein kinase G, an enzyme activated by cyclic GMP, which phosphorylates specific substrates. Greengard’s team further discovered new forms of CaMK, including CaMKII, which plays a role in phosphorylating synaptic proteins. His later work included identifying various protein phosphatases, which remove phosphate groups. Greengard also dedicated efforts to understanding the molecular processes behind the formation of plaques observed in Alzheimer’s disease and explored why certain brain cells are more susceptible to neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, while others demonstrate resilience.
Enduring Influence on Neuroscience and Medicine
Paul Greengard’s discoveries provided a foundational understanding of how brain cells communicate at a molecular level, reshaping neuroscience. His research offered insights into how various drugs, including antipsychotics, hallucinogens, and antidepressants, influence nerve signals. The mechanisms of dopamine signaling, as elucidated by his work, are now understood to be implicated in conditions such as Parkinson’s disease, schizophrenia, depression, attention deficit hyperactivity disorder, and substance abuse.
The concept of protein phosphorylation as a central regulatory mechanism in neuronal function, often referred to as “Greengard cascades,” remains a core principle in modern neuroscience. His influence extends to current drug discovery efforts, helping to identify new targets for improved therapies. Beyond his scientific papers, Greengard was a dedicated mentor, training hundreds of students and postdocs who became leaders in academic medicine and neuroscience. He furthered his legacy by establishing the Pearl Meister Greengard Prize using his Nobel winnings, an award recognizing outstanding women in biomedical research.