Desensitizing interactions

of receptor desensitization. Mutations that strengthen this interaction are more resistant to desensitization, whereas disruption of dimerization promotes desensitization. Dimer interaction takes place between domain 1 of the ligand-binding core in each subunit. When these interactions are strong, These studies also explain the mode of action of a drug that promotes AMPA activation, cyclothiazide (CTZ). CTZ binding in the ligand-binding core of the receptor stabilizes the dimer interface, thus reducing receptor sensitivity to desensitization. ᭿ Desensitizing interactions he strength of synaptic responses is controlled by neurotransmitter receptor activation, deactivation, and desensitization. The structural basis of desensitization has not been well understood, but and colleagues are getting a T Dimer stability determines whether AMPA receptors are activated or desensitized. look at how subunit interactions determine whether glutamate receptors are activated or desensitized. AMPA-sensitive glutamate receptors can either be activated or desensitized upon glutamate binding. Desensitization, in which the receptor is bound to ligand but inactive, allows for rapid cessation of signaling in the presence of agonist. AMPA receptors are arranged as heterotetramers, but Gouaux's group has determined that the functionally relevant structure for the ligand-binding core for desensitization is that of dimers of dimers. Using crystallographic and functional analyses of site-directed mutant subunits of GluR2, they show that the stability of the dimer interface at the ligand-binding core correlates linearly with the extent Slow and steady moves the cell ore actin-based protrusion should mean more cell movement, or so it has been thought. Yet depletion of the Ena/VASP family of actin-binding proteins, which promote lamellipodial protrusion rates, actually causes cells to M move faster. New results from and colleagues explain this counterintuitive effect by putting the emphasis on the quality rather Increasing amounts of Ena/VASP (left to right) change the actin architecture. than the quantity of protrusions. The group boosted Ena/VASP levels at the plasma membrane of fibroblasts and saw increases in protrusion velocity. But the protrusions were quickly withdrawn as ruffles. Within these lamellipodia, actin filaments were longer and less branched than normal and ran parallel to the membrane instead of perpendicular. " This tells us that the geometry of actin conformational changes induced by glutamate binding are more likely to take place by movement of domain 2. This movement forces open the channel of the receptor. Weaker dimer interactions make it more likely that domain 1 will move upon glutamate binding, breaking the dimer interface. When that happens, the …