The strength of synaptic responses is controlled by neurotransmitter receptor activation, deactivation, and desensitization. The structural basis of desensitization has not been well understood, but Yu Sun, Rich Olson, Eric Gouaux (Columbia University, New York, NY), and colleagues are getting a look at how subunit interactions determine whether glutamate receptors are activated or desensitized.
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 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, 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 channel is left closed, and although the receptor is bound, Na+ ions cannot pass.
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. ▪