THE MULTIPLE PHENOTYPES OF ALLOSTERIC RECEPTOR MUTANTS

Channel-linked neurotransmitter receptors are membrane-bound heterooli gomers made up of distinct, although homologous, subunits. They mediat e chemoelectrical signal transduction and its regulation via interconv ersion between multiple conformations that exhibit distinct pharmacolo gical properties and biological activities. The large diversity of fun ctional properties and the widely pleiotropic phenotypes, which arise from point mutations In their subunits (or from subunit substitutions) , are interpreted in terms of an allosteric model that incorporates mu ltiple discrete conformational states. The model predicts that three m ain categories of phenotypes may result from point mutations, altering selectively one (or more) of the following features: (i) the properti es of individual binding sites (K phenotype), (ii) the biological acti vity of the ion channel (gamma phenotype) of individual conformations, or (iii) the isomerization constants between receptor conformations ( L phenotype). Several nicotinic acetylcholine and glycine receptor mut ants with complex phenotypes are quantitatively analyzed in terms of t he model, and the analogies among phenotypes are discussed.