Channel changes customers

Channel changes customers W ith the right stimulation, an ion channel changes its stripes, say Man-Kyo Chung, Ali Guler, and Michael Caterina (Johns Hopkins School of Medicine, Baltimore, MD). Even ion channels that are a little promiscuous have their favorite passengers. Such channels were generally thought to stay true to their preferred customers. But Chung et al. found that the TRPV1 channel of painsensing neurons was more fi ckle. TRPV1 opens its gates when it binds to the chili pepper compound, capsaicin. The new electrophysiology experiments showed that, upon fi rst opening, the channel mostly let through small cations, such as calcium and sodium. But over time, the channel became more permissive to larger cations. The channel also tweaked its preference for calcium over sodium. When extracellular calcium levels were high, the channel’s preference for calcium waned with time. But if calcium levels were low, its calcium preference further increased. The alterations probably stem from structural changes upon capsaicin binding. Heat and camphor also open the channel, but they did not have such a strong effect on passenger preferences. TRPV1 phosphorylation, by contrast, amplifi ed the selectivity changes. “This is another layer at which the details of ionic fl ux into the cell can be regulated,” says Caterina. It is not clear, however, which large cations that might enter through TRPV1, such as spermidine, are physiologically relevant to neurons. Chung, M.-K., et al. 2008. Nat. Neurosci. doi:10.1038/nn.2102. Pseudokinase is active after all D on’t judge a book—or a kinase—by its cover, based on new fi ndings from Konark Mukherjee, Thomas Südhof (University of Texas Southwestern Medical Center, Dallas, TX), Markus Wahl (Georg-August-University, Göttingen, Germany), and colleagues. The group shows that a kinase predicted to be inactive has plenty of phosphorylation power. This not-so-disabled kinase is CASK. CASK lacks the residues needed to coordinate magnesium, which was thought to be required to transfer phosphates. But the new fi ndings suggest that CASK works without magnesium. The group’s new crystal structure of CASK adopted a conformation that is characteristic of constitutively active kinases. And it contained a pocket that looks like it should bind very well to ATP. “It would be weird,” says Südhof “for CASK to bind ATP and have an active conformation but be inactive.” The group thus thoroughly tested its kinase abilities. Even in the absence of magnesium, CASK phosphorylated one of its known binding partners, a synaptic adhesion molecule called neurexin-1. The biological outcome of the modifi cation is not known. CASK probably has several other substrates, as it is widely expressed and contains a protein-interacting scaffolding domain. Several pseudokinases similarly lack magnesium coordination centers. At least some of these proteins might have previously overlooked phosphorlyation skills. Mukherjee, K., et al. 2008. Cell. 133:328–339.