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PERSPECTIVES |
1 Department of Anaesthesiology, Washington University, Campus Box 8054, 660 South Euclid Ave., St Louis, MO 63110, USA Email: jhs{at}morpheus.wustl.edu
The glycine-gated receptor is a member of the nicotinic receptor family, often overshadowed by its cousins the nicotinic, GABA-ergic and even serotonin type 3 receptors. Glycine receptors are found in many regions of the nervous system (Lynch, 2004), but are best known as the targets for the convulsant poison strychnine. By blocking glycine receptors in the spinal cord, strychnine produces tonic paralysis. In humans and laboratory animals, the major feature of deficient glycine receptor expression or function is an exaggerated response to sudden stimuli, or excessive tone in muscles. One of the spontaneous mutations identified in mouse is named spasmodic, which produces tremor, exaggerated startle and some gait abnormalities. This results from a missense mutation in the glycine receptor 
1 subunit, A52S. Spasmodic is a loss-of-function mutation, and results in a shift in the concentration–response relationship to larger concentrations of glycine and a more rapid decay of responses (Graham et al. 2006). In an article in this issue of The Journal of Physiology, Plested et al. (2007) explore in elegant kinetic detail the functional deficit produced by this mutation, resulting in a very interesting insight into the repertoire of mechanisms for reduction of receptor activation.
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Plested et al. (2007) demonstrate that the functional abnormality in the spasmodic receptor is a consequence of an effect on the closed channel isomerization from AiC to AiF. The effect can be stated in two ways. First, in the spasmodic receptor the equilibrium ratio of AiF to AiC changes very little between singly and triply liganded receptors (only 
3-fold, versus 5000-fold for wild-type receptors). Second, the affinity for glycine in the flipped state is reduced in the spasmodic receptor (to 800 µM from 8 µM), and the affinity in the flipped state is only 2-fold better than in the resting state, as compared to 65-fold. The predicted activation curve is shifted to higher concentrations of glycine, as observed. When miniature inhibitory postsynaptic currents are simulated they are predicted to decay more rapidly, also as observed. A possible reason for the more rapid decay is that the rate for moving from A3F to A3C is increased 6-fold while the channel opening rate from A3F is reduced 2-fold in the spasmodic receptor. Finally, the spasmodic receptor also shows less change in apparent glycine affinity as a function of occupancy (less apparent cooperativity in binding). Burzomato et al. (2004) argued that the existence of the flipped conformation provides a plausible explanation for the observed apparent cooperativity: the concerted conformational change allows (un)occupied sites to sense the occupancy of relatively distant sites. Accordingly, the deficit in the flipped conformation provides a simple and elegant explanation for the reduced cooperativity.
So, receptor function can be compromised (and possibly enhanced?) not only by effects on resting or open channel receptors, but by an action on an intervening state. The duration of the closed dwells associated with the flipped conformation appears to be longer for the glycine receptor than for other family members, but it seems plausible that analogous states are present for other receptors. Indeed, an interposed closed channel transition in the activation pathway has been postulated for NMDA (Banke & Traynelis, 2003) and GABAA (Lema & Auerbach, 2006) receptors. Hence, this mechanism may not only be new, but may prove applicable to additional situations.
References
Banke TG & Traynelis SF (2003). Nat Neurosci 6, 144–152.[CrossRef][Medline]
Burzomato V, Beato M, Groot-Kormelink PJ, Colquhoun D & Sivilotti LG (2004). J Neurosci 24, 10924–10940.
Graham BA, Schofield PR, Sah P, Margrie TW & Callister RJ (2006). J Neurosci 26, 4880–4890.
Lema GM & Auerbach A (2006). J Physiol 572, 183–200.
Lynch JW (2004). Physiol Rev 84, 1051–1095.
Plested, Groot-Kormelink, Colquhoun & Sivilotti (2007). J Physiol 581, 51–73.
Related Article
1A52S in recombinant rat glycine receptors
J. Physiol. 2007 581: 51-73.
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