David Colquhoun - Scientific Career - Intermediate Shut States

Intermediate Shut States

All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957, in which the receptor existed in only two conformations, open and shut. It was only when the glycine receptor was investigated that it was realised that it was possible to detect an intermediate shut state (dubbed the "flipped" conformation), between the resting conformation and the open state. Subsequently it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al. (2008) found that partial agonists were partial, not, as had been supposed since 1957, because of a deficiency in the open reaction itself, but because of a deficiency at an earlier stage, a reluctance to move from the resting conformation to the intermediate shut state that precedes opening. The actual shut-open conformation change turned out to be much the same for partial agonists as it was for full agonists. In the original formulation the flipping reaction was supposed to be a concerted transition. The essentials of this new mechanism were confirmed by Mukhtasimova et al. (2009), who generalised it to the case where the subunits can flip independently.