The acetylcholine receptor (AChR) in skeletal muscle is normally confined to the end plate, but during development and after denervation, AChRs also occur throughout the entire membrane of muscle fibers. These extrajunctional receptors (EJR) differ in their functional, biochemical, and immunological properties from junctional receptors (JR), and are thought to play a role in the early stages of synapse formation. Our research is aimed at understanding how the two receptors are related biochemically, how their functional properties are determined, and what roles the two receptors play in synaptogenesis. We have previously shown that patients with myasthenia gravis contain in their serum antibodies that recognize determinants found only on the EJR. We have idenfified one serum that is unusually specific: in the rat, it recognizes only the toxin-binding site of the EJR. We will purify the relevant antibodies from this serum and use them to study the role of the EJR in development. We will investigate when the AChRs change their properties, how this change is regulated, and how the change in immunological properties is related to developmental changes in AChR clustering, metabolic turnover time and channel open time. Finally, we will use AChR from Torpedo electric organ to investigate the biochemical structure of the antigenic site recognized by this determinant. We will carry out a similar series of investigations with respect to another known molecular change in the AChR that occurs during development, the shift to a more acidic isoelectric point. We will study the developmental time course of this shift, its regulation and its relation to functional properties. We will also determine whether or not this change is distinct from the change in immunological properties, and if so, whether hybrid species of AChRs occur during development. Finally, we will study phosphorylation of the AChR in vitro and its relation to the functional and molecular changes that the AChR undergoes during development. Our investigations thus aim to elucidate the molecular mechanisms of differentiation of the postsynaptic muscle membrane during synaptogenesis.
| Yu, X M; Hall, Z W (1994) Amino- and carboxyl-terminal domains specify the identity of the delta subunit in assembly of the mouse muscle nicotinic acetylcholine receptor. Mol Pharmacol 46:964-9 |
