Oscillating calcium concentrations in the nuclei of liver cells translate insulin's signals into operating instructions.

Insulin receptors, shown in green, coat liver cells.

How does your body regulate its 50 trillion cells? The short answer is that it sends chemical messages to tiny subassemblies operating inside each one of them. Despite decades of study, however, intracellular communications are only dimly understood. Now a team led by HHMI international research scholar Maria de Fátima Leite has discovered an elegantly simple explanation for one of these command mechanisms.

In the November 2008 issue of Hepatology, the researchers describe for the first time the transfer of information from insulin to calcium ions in liver cell nuclei. Because it regenerates even after severe damage, the liver could be a key to explaining both normal cell growth and cancer. And calcium is a known “second messenger,” decoding commands like “Die!” or “Grow!”—carried through the bloodstream by hormones such as insulin—into language that the cell's subsystems understand.

“We've known for a long time that insulin affects regeneration,” Leite says. “We've also known that insulin changes calcium concentrations in the cytoplasm, the part of the cell surrounding the nucleus. But we'd never seen insulin receptor in the nucleus itself.”

Detecting insulin receptors in the same places and at the same times as rising and falling calcium concentrations told the researchers they had made two discoveries, says Leite: “One, insulin causes calcium oscillations in the nucleus; and two, receptors translocate from the cell wall to the nucleus, traveling much deeper than we had thought.”

Although a receptor is submicroscopic, Leite says, at the cellular scale its dive to the nucleus is an epic one. “If you imagine a receptor molecule as a two-meter-tall lifeguard, the distance would be something like swimming the length of Lake Titicaca.”

Both discoveries are far more than just scientific curiosities, she says. “These are very important clues to specific problems. If we can learn to stimulate calcium oscillations in the nucleus, in a way that switches on regeneration or inhibits tumor growth, we may be able to design finely targeted medications with fewer side effects.

“And the beauty here is that the explanation is so simple. In science, the simplest explanation tends to be the right explanation.”

Photo: Hepatology, Vol. 438, No. 5, 2008, cover. © 2008 John Wiley & Sons, Inc. Reprinted with permission of John Wiley & Sons, Inc.