STRUCTURAL AND FUNCTIONAL ANALYSIS OF AGRIN PROTEINS

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The ability to process sensory information and express complex behaviors depends on rapid communication between electrically excitable cells in the nervous system. Signalling between electrically excitable cells is largely accomplished by chemical synapses. Understanding the cellular and molecular organization of chemical synapses and the rules that control their development and maintenance are therefore central questions in modern neurobiology. The neuromuscular junction is a useful model system in which to address these questions. Like other chemical synapses, the neuromuscular junction consists of precisely registered pre-and postsynaptic elements, each specialized for their role in synaptic transmission. In particular, the postsynaptic muscle motor end- plate has high concentrations of receptors (AChR) for the neurotransmitter acetylcholine, and acetylcholinesterase (AChE), an enzyme responsible for its breakdown. Extracts of the synapse-rich electric organ of the electric ray induce the formation of patches on muscle fibres in vitro that contain both AChR and AChE, mimicking the accumulation of these post-synaptic components that occurs during normal development. Four structurally related proteins have been purified from the electric organ extract of which two, called agrin, are able to induce the formation of AChR/AChE aggregates. The remaining two agrin-like proteins however are not active by this assay. Molecules related or identical to agrin are present at the neuromuscular junction, suggesting that agrin proteins play a role in its development and maintenance. The presence of molecules similar to agrin in other tissues suggests that agrin proteins may have additional important functions. The goal of this proposal is to characterize agrin proteins at the molecular level and define the structural basis for their physiological properties. This will add to our understanding of the mechanism of agrin protein action and the molecular events occurring during synaptogenesis. These goals will be realized through biochemical and immunological analyses of native proteins and by complementary molecular studies of agrin genes and their products. These studies will enhance our ability to alleviate developmental anomalies in synaptogenesis and potentiate neuromuscular regeneration following trauma.