Editors' ChoiceIon Channel Dynamics

Structure and Function

+ See all authors and affiliations

Science's STKE  21 May 2002:
Vol. 2002, Issue 133, pp. tw187-TW187
DOI: 10.1126/stke.2002.133.tw187

Many ligand-gated ion channels that are activated upon binding to neurotransmitter molecules become inactivated, or desensitized, shortly after the transmembrane pore of the channel opens. This phenomenon is particularly important in fast chemical synapses of the nervous system where the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) and kainate-type glutamate receptors desensitize in milliseconds. However, it has not been clear how desensitization occurs when agonists are still tightly associated with the receptor. Su et al. provide some structural insight into the coupling of activation and desensitization of the GluR2-type AMPA receptor. The receptor consists of four transmembrane subunits, and glutamate-binding pockets are formed at dimer interfaces. Isolated glutamate-binding regions of the AMPA receptor showed less of a tendency to dimerize than did a form harboring a mutation known to block desensitization. A mutation that accelerates desensitization reduced dimer affinity. The authors explain this inverse correlation by proposing that a conformation change in the ligand-binding pocket may induce a conformational change within the transmembrane domains that forces the ion channel to open. However, the tension generated stimulates a subsequent conformational change in the ligand-binding region to relieve this tension. This uncouples the ligand-binding region from the channel region and permits the ligand-associated desensitized state. Hence, the interface between dimer subunits appears to control receptor activation and desensitization.

Although structural and functionally similar to AMPA receptor, it has not been clear whether neuronal kainate receptors exhibit conductance properties that reflect increasing amounts of individual subunit activation, as seen with AMPA receptors. Through site-directed mutagenesis and use of a high-affinity agonist, Swanson et al. demonstrate that kainate receptors comprising GluR5 and KA-2 subunits do behave like AMPA receptors in that there are indeed subunit-associated conductances. The authors identify high- and low-affinity agonist-binding sites on the GluR5 and KA-2 subunits, respectively, Occupation of two pharmacologically separable ligand-binding sites may underlie the complex channel sensitivities and activation and desensitization kinetics displayed by these heteromeric glutamate channels.

Y. Sun, R. Olsom, M. Horning, N. Armstrong, M. Mayer, E. Gouaux, Mechanism of glutamate receptor desensitization. Nature 417, 245-253 (2002). [Online Journal]

G.T. Swanson, T. Green, R. Sakai, A. Contractor, W. Che, H. Kamiya, S.F. Heinemann, Differential activation of individual subunits in heteromeric kainate receptors. Neuron 34, 589-598 (2002). [Online Journal]

Related Content