LAUSR

I first met Paul Greengard in September 1974. I had just returned to Yale College for my junior year after having spent the prior summer at Rockefeller University as a research volunteer where I studied regulation of cyclic GMP synthesis in the exocrine pancreas. As part of that project, I learned that Paul, then a professor of pharmacology at Yale, was a leader in cyclic nucleotide research. I thus made an appointment to meet with Paul when I returned to campus in the hope of doing a senior research thesis in his laboratory. I was told by his secretary to knock on his office door and enter and, when I did, I was faced by two large huskies—glaring at me head on from less than five feet away; Paul was nowhere to be seen. Suddenly, from behind the desk, I heard Paul say: “Come on in. They won’t bother you.” Paul was lying flat on his back on the floor of his office working on a manuscript—something he did often in those days to nurse a bad back. The rest, as they say, is history. I completed my senior thesis in the Greengard laboratory and stayed on at Yale for my M.D.-Ph. D. training most importantly so that I could do my graduate work with Paul. Paul became a second father to me and we remained very close—both scientifically and personally—until his recent death on April 13, 2019 at the age of 93. From a scientific perspective, it is difficult to overstate the impact that Paul had on our understanding of cell signaling in general, and in the nervous system in particular. In the 1970s, the field of neuroscience was focused primarily on the control of the electrical activity of nerve cells and the ability of one nerve cell to affect the electrical activity of other nerve cells through synaptic transmission. Synaptic transmission itself was viewed as a primarily electrical phenomenon, whereby neurotransmitters controlled the opening and closing of postsynaptic proteins that served as ligand-gated or voltage-gated ion channels. In the background, there was an associated field of “neurochemistry,” with investigators focused on the biochemical composition of brain tissue with limited regard for the underlying neural circuitry. Paul once told me that these two approaches to the nervous system operated almost completely separately with very limited crosstalk, and in fact that many of the leaders of each approach did not much like one another either! Paul saw the world differently. In 1968, Ed Krebs, Ed Fischer, and colleagues discovered cyclic AMP-dependent protein kinase (protein kinase A) in peripheral tissues, which they showed mediated the ability of circulating glucagon and epinephrine to stimulate glycogenolysis. Paul’s son Leslie reports that when Paul saw that discovery he posited that the brain operates in the same way—that neurotransmitters also act in part like peripheral hormones—and that he was going to prove it. And that’s exactly what he did over the ensuing five decades. Paul spent most of his early career at the pharmaceutical company Geigy and, after brief sabbaticals at Vanderbilt University and at Albert Einstein College of Medicine in 1968, he joined the Yale pharmacology department in 1969 to establish his first academic laboratory at the age of 43. He quickly set out to test his hypothesis, first by showing that protein kinase A is expressed at high levels in brain, including synaptic fractions, and demonstrating in brain tissue the existence of substrates for protein kinase A that were not detectable in peripheral tissues. One of the first substrates discovered was named “Protein 1” (classic Paul!). Parenthetically, Protein 1 was the subject of my Ph.D. thesis in Paul’s laboratory years later; my small part of the story was to demonstrate that Protein 1 phosphorylation is regulated by nerve impulses, thereby directly linking a nerve cell’s electrical activity to a biochemical process in a defined circuit. The later demonstration that Protein 1 is enriched at synapses and associates with synaptic vesicles—for which it gained the new name, synapsin 1, lent further credence to Paul’s organizing hypothesis that protein phosphorylation contributes to synaptic transmission. This discovery also stimulated ensuing decades of research by numerous