hERG: Legs, Drugs, and Heartbeats

The Whisky-a-Go-Go, 1965, Los Angeles
Credit: WFMU Ichiban Radio

Recently, while scribing my drug design post for CENtral Science, I happened to notice some abbreviations towards the back of a J. Med. Chem. article. TNF - Tumor Necrosis Factor Alpha. (check). HCV - hepatitis C virus (check). hERG - human Ether-à-go-go Related Gene...


...what?!?


Yup. Biologists love a good play on words. Among the well-known Drosophila (fruit fly) genes are lush, sonic hedgehog, and methuselah*. In our bodies, certain drugs interact with the hERG receptor, one of several human homologues (close matches) to fly genes. But I hadn't realized that this PK point of conversation was named for a night club in L.A. 


Ever heard of a "go-go" dancer? 


Urban legend holds that famed club Whisky a Go-Go, a 1960s rock music hotbed, first institutionalized the profession when it opened on the Los Angeles Sunset Strip. To capitalize on a popular trend from New York and Paris, the owners set girls to "go-go" dancing in large cages suspended from the ceiling.

Not a Drosophila geneticist.

What's "go-go" dancing, you ask? Think of the female silhouettes you see before movies like James Bond, or better yet later spoof Austin Powers: International Man of Mystery - Tall boots, short skirts, and lots of hip shakes and leg twists. So, what does this have to do with fruit flies, or human drug testing?


As recounted in a 1991 Science News feature, neurogeneticist William Kaplan first noted the ether-à-go-go (eag) mutation in the 1960s. If these flies were knocked out with ether, their legs would twitch and shake, much like the famed dancers. When two researchers from the University of Wisconsin discovered similar mammalian genes, they took a page from the same book, naming them "erg," or "ether-à-go-go related genes."  

ECG of a single heartbeat
Source: Wikipedia Commons | Agateller

Warmke and Ganetsky, the two Wisconsin geneticists, found that the hERG gene encoded specific voltage-gated potassium channels in cell membranes (i.e., they open and close to allow potassium ions to flow out of the cell). In heart cells, these channels control the back-end of the heartbeat, the so-called "QT interval" (see graphic). When drugs block these channels, cardiac membrane repolarization (electrical charge balancing) takes longer, and a fatal arrhythmia may set in.

Seldane (terfenadine)

Anyone remember Seldane (terfenadine)? In the late 1980s, allergy sufferers praised it as a non-sedating antihistamine. However, it became a hERG poster child, and the FDA recommended its removal from the market in 1997. 


*Decoder ring: lush mediates alcohol response, sonic hedgehog (shh) controls organ and limb differentiation, and methuselah creates long-lived flies