From Worms to People

It is hard to overestimate the importance of G protein-coupled receptors (GPCRs) and their cognate G proteins. They seem to be everywhere in the human body, regulating heart rate; basic endocrine function; the senses of sight, smell and taste; pain tolerance and even the high of cocaine. And that's just for starters. Sequence homology data suggest that there are hundreds, perhaps thousands, of GPCRs still to be identified in the human genome. Five percent of the genome of the worm C. elegans, one of the first model organisms to be sequenced entirely, for example, consists of genes for GPCRs, says Henrik Dohlman, a former Lefkowitz protégé who is now an associate professor of pharmacology at the Yale University School of Medicine.

It might seem that in view of how long GPCRs have been studied and the many scientists now working in the field, there would be no more room for innovation. But nothing could be further from the truth, says Lefkowitz. Even after all these years, the field continues to produce many surprises.

Three years ago, a genetic variation was discovered that protects some people from developing AIDS despite repeated exposure to HIV. The variation turned out to be a slight modification of a molecule called CC-chemokine receptor 5 (CCR5), the GPCR that HIV usesto enter a T cell, which is its preferred entry point into the immune system. In separate work, Dan R. Littman, an HHMI investigator at New York University Medical Center, and Ed Berger at the National Institutes of Health showed that CCR5 is a co-receptor for HIV. Suddenly the world of HIV research came knocking on Bob Lefkowitz's door, and he found himself speaking before international AIDS conferences.

As with AIDS, so with epilepsy. Lee Limbird, Lefkowitz's first postdoc, is exploring a weak "agonist" or activator of the b₂ subtype receptor to control that disease. She and her colleagues at Vanderbilt University are starting a clinical study to see if clonidine, a blood pressure medication, can reduce the frequency of epileptic seizures. Other research in her lab suggests that weak partial GPCR agonists can lower blood pressure without sedative side effects. "The clinical applications seem unlimited," she says. Right now, fully half of all prescription medications work through the GPCR cascade, she points out.

And just this year, HHMI investigators Charles Zuker at the University of California, San Diego, and Linda Buck at Harvard Medical School, working separately, identified the first human bitter taste receptors. No surprise: These, too, are GPCRs, as are a series of smell receptors that Buck and her colleagues previously identified. It is the way Buck found the smell receptors that illustrates the power of Lefkowitz's work. Her group launched its search of the genome under the assumption that the receptors would look like cousins to the GPCR family that Lefkowitz defined early in his career.

"I would say that over the last decade or so, Lefkowitz laid the groundwork that now allows us to expand the study of these receptors in many systems," says Buck—and there are literally thousands of varieties of GPCRs in the sensory systems alone.

In fact, the first GPCR to be identified and cloned, rhodopsin, translates light signals into images in the brain. It was Lefkowitz and his group who discovered in 1986 that bARs are strikingly similar to rhodopsin, exhibiting what has come to be called a "seven transmembrane structure"—a portion of the protein that snakes its way through the membrane seven times. When he further predicted that GPCRs would turn out to be a superfamily of receptors, he made quite a splash.

But that was then, and Lefkowitz has moved on. He is, after all, a clinician who still makes hospital rounds and, after 30-plus years of lab work, is ready to make a foray into the clinical arena.

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