Taking Things One Step at a Time

Science's STKE  05 Aug 2003:
Vol. 2003, Issue 194, pp. tw301-TW301
DOI: 10.1126/stke.2003.194.tw301

Most fast excitatory synaptic transmission in the brain is mediated by the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR), a ligand-gated ion channel. AMPARs comprise four subunits, each of which binds glutamate. Ligand binding promotes an open conformation, in which ions can pass through, whereas the unbound receptor is predominantly closed. Partial agonists activate the channel, allowing ions to pass through, but do not elicit as large a response as do full agonists. The mechanisms underlying this partial response have been unclear. Jin et al. investigated the effects of a series of partial agonists on AMPAR structure and conductance. High-resolution crystallographic analysis demonstrated that the glutamate-binding region assumed different conformations when bound to ligands that differed in the size and electronegativity of a single atom; shifts in conformation were graded and depended on the size of the substituted atom. Single-channel analysis revealed the existence of three different conductance states. The frequency with which the different conductance states occurred correlated with the efficacy of the agonist (and the size of the substituent). The authors concluded that the ligand-binding region can assume various conformations that affect the probability of discrete subconductance states, consistent with a model of channel activation in which the four subunits gate independently and each contributes incrementally to channel opening. The efficacy of partial agonists depended on the extent to which they promoted one or another of these states, rather than on differences in their ability to shift the channel from a single "closed" state to a single "open" state. Weiss and Chang provide useful background information and caution against extrapolating the conclusions to the pentameric family of ligand-gated ion channels.

R. Jin, T. G. Banke, M. L. Mayer, S. F. Traynelis, E. Gouaux, Structural basis for partial agonist action at ionotropic glutamate receptors. Nat. Neurosci. 6, 803-810 (2003). [Online Journal]

D. S. Weiss, Y. Chang, Crystallizing our understanding of partial agonists. Nat. Neurosci. 6, 788-789 (2003). [Online Journal]