Promiscuous G, you're teasing me.

I read this paper for a literature meeting nearly a month ago and I had meant to blog about it at the time. Here's the reference:
"Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake"
Science 2005, 310, 996-999.
Obestatin is a hormone that suppresses food intake and weight gain in mice (thanks to Harriet for the picture of the cute little mousie), so you can imagine that a lot of news outlets picked up the story when the paper came out last year. The message there was that finding obestatin provides a new drug target that could allow researchers and physicians to rein in that 10 AM candy bar craving in the not-too-distant future.

The work was fascinating to many researchers, not as the next big obesity cure, but because ghrelin and obestation come from the same gene and appear to have opposite effects! (Ghrelin increases body weight in mice.) The paper's authors first had a hunch that obestatin would exist because they performed a computer search of extensive genome sequence data for genes that look like they code for hormones. This touches off a debate on how much of an effect genomics has really had on the way we conduct research. See this post at In the Pipeline for commentary.

When I read this paper, I was drawn to the discovery that obestatin activates something called an "orphan G-protein-coupled receptor". Receptors are proteins that relay signals in the body in order to achieve some downstream effect, like muscle contraction. The human genome sequence has turned up a couple hundred genes that encode "G-protein-coupled receptors", a specific family of receptors with a track record of being valuable drug targets. Researchers don't yet know what interacts with "orphan receptors", but they'd eventually like to correlate them to a particular pathway or disease, so that they can eventually develop new and better drugs. That's why obestatin was such a big deal in the health field.

I guess this paper got me to thinking, "Isn't there a more proactive way to find the ligands (partners) for these orphan receptors instead of just waiting around for someone to publish papers like this one a couple of times a year?"

There are several ways that researchers go about this systematically. Scientists can take a little of the guesswork out of what the ligand is based on how similar the orphan receptor is to the ones we already know. Screening lots of potential partners at once is possible by coupling the receptor-ligand interaction to some kind of readout. The "adapter" they use is a G protein. Yes, these receptors are coupled to a G protein that sends out a message on its behalf. That's where the name "G-protein-coupled receptor" comes from.

So, why a promiscuous G protein? Promiscuous G's can speak for a wide range of receptors. It's much easier to set up the experiment if you don't have to change multiple components. Just get the new receptor that you want to test and all the other pieces are ready to go.

Unfortunately, there's no "universal adapter" quite yet. These screens are used often in drug discovery, but for now, scientists are getting by with an assortment of naturally occurring promiscuous G proteins and a few that they've engineered in the lab, and having to pick the one that works best for their system.

See these refs:
TRENDS Pharmacol. Sci. 2005, 26, 595-602.
Annu. Rev. Pharmacol. Toxicol. 2004, 44, 43-66.
Receptors and Channels 2002, 8, 297-308.
TRENDS Pharmacol. Sci. 2001, 22, 560-564.