Regulation of Biogenesis and Topogenesis of Acetylcholine Receptors

Suny At Stony Brook, Stony Brook NY

Investigators

Abstract

0082232 Prives Transmission of impulses from nerve to muscle is made possible by the existence of neuromuscular junctions; specialized sites of communication between motor neurons and skeletal muscle cells. The formation of these synapses during embryonic development depends on the intricate coordination between nerve endings and muscle cells. A striking aspect of this coordination is the nerve-induced redistribution of acetylcholine receptors (AChRs), specialized membrane components that are initially uniformly spread on the muscle surface but become highly concentrated at postsynaptic muscle surfaces immediately under nerve endings. The objective of the studies described in this proposal is to identify the molecular mechanisms that trigger neuron-induced AChR clustering. The focus is on the role of a specific family of regulatory proteins - the Rho GTPases - as crucial mediators of AChR clustering. The planned studies will utilize cultured muscle cells to measure the effects of transfected Rho GTPase mutants on AChR surface distribution. Biochemical assays and fluorescence microscopy will be used to analyze the mechanisms by which the trans-synaptic signaling proteins agrin and laminin, as well as cultured neurons, activate the Rho GTPases and trigger AChR clustering. The overall aim of this study is to elucidate the molecular mechanisms that control neurotransmitter receptor site density at synapses. Regulation of receptor site density constitutes a potential mechanism for functionally altering neuronal circuits. Thus, in addition to increasing the understanding of how neuromuscular transmission is regulated, the proposed studies can yield information relating to the synaptic mechanisms underlying learning and memory.