April 27, 2007

Sutherland Lecture mixes ‘love potion,’ depression research

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Paul Greengard, Ph.D., delivers the Sutherland Lecture. (Dana Johnson)

Sutherland Lecture mixes ‘love potion,’ depression research

A funny thing happened on the way to discovery.

In early 2000, Paul Greengard, Ph.D., and his colleagues reported that a brain protein they'd been studying was required for sexual receptivity in female rats and mice.

The report, published by Science magazine just in time for Valentine's Day, triggered feverish news coverage. “Brain Protein Is Real Cupid's Arrow,” declared one headline, while others predicted a new “love potion” would soon be on its way to market.

During his Sutherland Lecture last week at Vanderbilt University Medical Center, Greengard, a Rockefeller University scientist and Nobel laureate, said he was not prepared for the onslaught.

“It slowed down my research significantly, answering the phone all day long,” he deadpanned, unleashing gales of laughter from his audience, which overflowed from a Light Hall lecture hall.

Since then, Greengard, who directs the Laboratory of Molecular and Cellular Neuroscience at Rockefeller, has reported that this highly conserved protein — called DARPP-32 — also mediates the actions of a wide range of drugs, from Prozac to LSD.

DARPP-32 stands for Dopamine- and cyclic-AMP Regulated Phosphoprotein-32.

When activated by the attachment of a phosphate group, a process called phosphorylation, DARPP-32 in turn increases the phosphorylation of other proteins in the brain involved in a host of physiological responses, from muscle control to mood.

The protein is part of the signaling pathways of major neurotransmitters, notably dopamine, glutamate and serotonin, and as such plays a role in everything from Parkinson's disease and attention deficit hyperactivity disorder (ADHD) to depression, schizophrenia and drug abuse.

Recently, Greengard and his colleagues have turned their attention to another protein, called p11, which interacts with the serotonin 1B receptor. Antidepressants and electroconvulsive therapy (ECT) increase p11 levels in mice brains, while animals lacking the gene for the protein exhibit depression.

Low p11 levels also have been found in the brains of deceased patients who suffered from depression. “Thus, genetic manipulation of p11 levels might affect behavior and regulate susceptibility to depression,” Greengard said.

While that doesn't mean a new drug for depression is around the corner, he cautioned, p11 could be a marker for depression.

Greengard credited Vanderbilt for influencing the direction of his career. As a young scientist in 1967, he worked briefly with the late Sidney Colowick, Ph.D., and Earl Sutherland Jr., M.D., VUMC's first Nobel laureate.

“It was an amazing, exciting time,” he said. “It had a major influence on my own thinking and subsequent work.”