Acetylcholine receptor biosynthesis: from kinetics to molecular mechanism

Abstract

The study of acetylcholine receptor (AChR) biosynthesis is currently in a transition period. New approaches and reagents have made it possible to explore previously inaccessible aspects of this problem. Formerly, studies of AChR synthesis treated the receptor as a single entity, defined solely by its ability to bind ligands such as α-bungarotoxin. Thus, our understanding of this complex process was inferred exclusively from measurements of the kinetics with which this entity moved through the cell and was inserted into the plasma membrane. However, as the result of extensive efforts at biochemical characterization of AChR, we now know that the protein is a tightly associated non-covalent complex of four large (approximate mol. wt 50 000) glycoprotein subunits, in stoichiometry α2βγδ (Ref. 13). The problem of AChR biogenesis must therefore be entirely reconsidered in the context of this new perspective. Questions have been raised relating to the synthesis of the individual subunits, theirinsertion into the membrane, and their assembly into a functional oligomeric complex. To approach these questions, it is necessary to examine directly the synthesis of the constituent AChR polypeptides. This has only recently become possible with the advent of AChR subunit-specific antibodies, both polyclonal and monoclonal. In this review, I shall describe how the use of these new reagents has allowed us to begin to think about the synthesis of AChR in terms of discrete, molecular events. However, it should become clear that the biogenesis of this important membrane protein is a much more complicated process than we originally thought.

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