A Close Look at Receptor Signaling

Ah, the good old central nervous system, and its good old receptors. Especially the good old ion channels - there's an area with enough tricky details built into it to keep us all busy for another few decades. Here's a good illustration, in a new paper from Nature Chemical Biology. The authors, from Berkeley, are looking at the ionotropic glutamate receptors, an important (and brainbendingly complex) group. These are the NMDA, AMPA, and kainate receptors, if you name them by their prototype ligands, and they're assembled as tetramers from mix-and-match subunit proteins, providing a variety of species even before you start talking about splice variants and the like. This paper used a couple of the simpler kainate systems as a proving ground.

They're working with azobenzene-linked compounds that can be photoisomerized, and using that property as a switch. Engineering a Cys residue close to the binding pocket lets them swivel the compound in and out (as shown), and this gives them a chance to see how many of the four individual subunits need to be occupied, and what the states of the receptor are along the way. (The ligand does nothing when it's not tethered to the protein). The diagram shows the possible occupancy states, and the colored-in version shows what they found for receptor activation.

You apparently need two ligands just to get anything to happen (and this is consistent with previous work on these systems). Three ligands buys you more signaling, and the four peaks t...

Source: In the Pipeline - February 27, 2014 Category: Chemists Tags: Biological News Source Type: blogs