October 24, 2007

Identification of a novel cellular messenger

Zinc acts as second messenger in the cell to propagate extracellular signals

Researchers from Japan have shown that zinc can be used by the cell to transduce extracellular signals into cellular responses by propagating intracellular signaling pathways.

Cells that comprise the tissues of many different systems in the body must respond to extracellular molecular signals, such as hormones, toxins, cytokines, and metabolic by-products, in order to generate an appropriate and coordinated response. These external stimuli are often blocked by the plasma membrane that surrounds these cells, so they rely on so-called ‘second messengers’ within the cell to propagate the signaling cascade from the cell’s exterior. Numerous reports indicate that certain small molecules play this role, the best studied being calcium.

Now Toshio Hirano at the RIKEN Research Center for Allergy and Immunology in Yokohama and his colleagues have added zinc to this list of second messengers1. The team’s findings elevate our understanding of the biological importance of zinc beyond its previously identified role as a neurotransmitter and a co-factor for protein folding and function.

Working with mast cells, which are immune cells involved in the allergic response, Hirano’s group showed that when they mimicked the immune activation of these cells by stimulating a membrane-bound receptor on their surface, a wave of zinc was generated that washed across the cell a few minutes after the stimulation (Vid. 1). They then showed that a rapid influx of calcium from outside the cell was required before this zinc-wave occurred. According to Hirano and his team, the zinc-wave seemed to originate from the endoplasmic reticulum, but they could not rule out other intracellular sources, such as the nucleus.

Investigating further, the researchers showed that one role of the zinc-wave, at least, is to inhibit an important class of enzymes that remove the activation signals from other signaling proteins. This inhibition extends the activation time of these signaling proteins and therefore allows the continuation of the cellular signaling cascade. In the case of the mast cells, this resulted in further expression of IL-6 and TNFα—two key immunoregulatory cytokines that, in turn, can influence the behavior of a number of other cell types.

Hirano hopes to perform future experiments that will determine the molecular mechanisms that coordinate calcium influx with intracellular zinc flow. Also in his sights is identifying other cell types that use zinc as a second messenger and the targets within those cells.


  1. Yamasaki, S., Sakata-Sagawa, K., Hasegawa, A., Suzuki, T., Kabu, K., Sato, E., Kurosaki, T., Yamashita, S., Tokunaga, M., Nishida, K. & Hirano, T. Zinc is a novel intracellular second messenger. Journal of Cell Biology 177, 637–645 (2007). | | (Link)