Neurotransmitters, which diffuse across the synaptic cleft to bind to postsynaptic receptors that act as ligand-gated ion channels, mediate rapid signaling between neurons. However, the mechanisms whereby ligand binding--which occurs some distance from the transmembrane channel domain--is transduced into channel opening has been unclear (see Czajkowski). Now two groups have shed light on the mechanism through which ligand binding activates the nicotinic acetylcholine receptor (nAChR) and the 5-hydroxytryptamine type 3 (5-HT3) receptors (both members of the Cys-loop family of ligand-gated ion channels). Using an atomic scale model of the Torpedo nAChR to identify likely residues, Lee and Sine combined single-channel recording with mutational analysis to define a series of interacting amino acids that link ligand binding to channel gating. One of the amino acids in this linkage pathway is a proline, and a proline at the same location (the top of the loop between the M2 and M3 transmembrane helices) in the 5-HT3 receptor was the focus of a study by Lummis et al. Proline can exist in either a cis or a trans conformation and, by performing voltage-clamp analysis on Xenopus oocytes that expressed mutant receptors in which this proline was substituted by analogs with different preferences for the cis or trans conformation, Lummis et al. determined that preference for the cis conformation favored the open state, whereas preference for the trans conformation led to nonfunctional closed channels. Thus, the results of the two studies suggest that ligand binding initiates a series of amino acid movements that lead to a switch in proline from the trans to the cis conformation and opening of the channel.
W. Y. Lee and S. M. Sine, Principal pathway coupling agonist binding to channel gating in nicotinic receptors. Nature 438, 243-247 (2005). [PubMed]
S. C. R. Lummis, D. L. Beene, L. W. Lee, H. A. Lester, R. W. Broadhurst, D. A. Dougherty, Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 438, 248-251 (2005). [PubMed]
C. Czajkowski, Neurobiology: Triggers for channel opening. Nature 438, 167-168 (2005). [PubMed]