Agrin is an extracellular matrix protein that directs the accumulation of acetylcholine receptors in the postsynaptic apparatus of the developing neuromuscular junction. Agrin is also expressed by neurons in the central nervous system (CNS), but its function is less well defined. For example, in addition to a role as a postsynaptic organizer, agrin has also been implicated in regulating the differentiation of axon terminals as well as growth and branching of axons and dendrites. As an alternate approach to understanding agrin function in the CNS, we have focused on identifying signal pathways through which agrin might act. These studies recently discovered a neuronal receptor for agrin, concentrated at neuron-neuron synapses, and distinct from the muscle specific kinase complex that mediates agrin's action in muscle. Agrin binding to this receptor triggers a rapid increase in intracellular calcium and activates calcium/calmodulin-dependent kinase II and other kinases known to regulate synaptic function. Here we provide evidence the agrin receptor is a 100 kDa membrane tyrosine kinase. Chronic inactivity of this receptor results in decreased neuronal responses to excitatory neurotransmitters, correlated with alterations in calcium homeostasis. To learn more about agrin's function in brain, we will establish the molecular identity of the agrin receptor; characterize the cellular interactions that regulate its expression; examine the effects of suppressing agrin receptor expression and; identify mechanisms by which agrin influences neuronal responses to excitatory stimuli. The experiments outlined here are aimed at understanding the cellular mechanisms that control behavior of neural circuits in brain. Agrin, a molecule critical for neuromuscular connectivity, is required for development of normal responses to excitatory neurotransmitters. In light of our earlier demonstration that expression of agrin is activity dependent, agrin may prove to be a key modulator of neuronal activity in brain. The results of these studies, therefore, are likely to be directly relevant to the prevention and treatment of a number of human disorders, such as epilepsy, that disrupt behavior of neural circuits.
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