Dept.: Professor and Chair, Department of Physiology & Biophysics
Neuroscience Focus Group:
Synaptic transmission in the nervous system depends on highly specialized distributions of ion channels and other proteins for speed and specificity. Receptors for neurotransmitters are anchored at postsynaptic sites, where they bind the transmitter and cause a depolarization (at excitatory synapses) or a hyperpolarization (at inhibitory synapses). Strong evidence suggests that the association between receptors and intracellular membrane-associated proteins is an important feature of these specializations. Binding partners have been identified for several transmitter receptors. These include nicotinic acetylcholine receptors and rapsyn, glycine receptors and gephyrin, NMDA glutamate receptors and PSD-95, and AMPA glutamate receptors and GRIP. In many cases, the binding partner is also a scaffolding protein that links the receptor to signaling proteins, thus forming a complex of functionally interactive proteins. We study the synaptic scaffolding complex formed by dystrophin, the product of the Duchenne muscular dystrophy gene. The dystrophin complex is highly concentrated postsynaptically at the neuromuscular junction, and at some central nervous system synapses, including the outer plexiform layer of the retina. The syntrophins, which are modular adapter proteins, comprise one family of dystrophin-associated proteins. Of the five forms of syntrophin encoded by separate genes, one form is highly localized at the neuromuscular synapse and at synapses in the retina. Syntrophins bind important signaling proteins: nNOS, voltage-activated sodium channels, aquaporins, stress-activated kinase-3 (also known as p38) and a microtubule-associated serine/threonine kinase. Current research involves the search for additional syntrophin binding proteins, the investigation of the importance of syntrophin in sodium channel and nNOS localization at synapses, and the importance of syntrophins in neuronal function, especially in the retina. To study the in vivo function of syntrophins, we have produced mice lacking syntrophins. Mice lacking alpha-syntrophin have aberrant neuromuscular junctions with low amounts of nicotinic receptors and acetylcholinesterase. By combining genetic and molecular biological approaches, we hope to understand the mechanisms involved in producing the membrane specializations required for synapse formation and function.