Paul Greengard

Greengard showed that neurotransmitters like dopamine exert their effects through a process called slow synaptic transmission, in which the neurotransmitter activates receptors that trigger intracellular protein phosphorylation cascades rather than directly opening ion channels. He demonstrated that dopamine binding to D1 receptors activates protein kinase A, which then phosphorylates downstream target proteins like DARPP-32. This explained how dopamine produces long-lasting changes in neuronal function relevant to movement, reward, and cognition.

Greengard shared the 2000 Nobel Prize in Physiology or Medicine with Arvid Carlsson of the University of Gothenburg and Eric Kandel of Columbia University. Carlsson was recognized for establishing dopamine as a neurotransmitter in the brain, Greengard for detailing the intracellular signaling cascade that dopamine triggers, and Kandel for showing how these molecular mechanisms underlie memory formation in the sea slug Aplysia.

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) is a protein that Greengard's lab at Rockefeller University discovered as a major target of dopamine-activated protein kinase A in the brain. Once phosphorylated, DARPP-32 itself becomes an inhibitor of protein phosphatase-1, amplifying the dopamine signal by preventing the dephosphorylation of other downstream proteins. Greengard showed that DARPP-32 acts as a central hub integrating multiple neurotransmitter signals, making it critical for understanding how drugs like antipsychotics and drugs of abuse work.

Greengard spent the latter half of his career at Rockefeller University in New York, where he was the Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. Before joining Rockefeller in 1983, he held positions at Yale University and the Geigy Research Laboratories. His Rockefeller lab remained active in studying the molecular basis of neurological and psychiatric diseases until his death in 2019.