Neurogranin and neuromodulin (GAP-43) are neurospecific calmodulin (CaM) binding proteins that may play important roles for regulation of neuron growth by regulating the levels of free CaM within neurons. Although the overall sequence of the two proteins show low homology, neurogranin contains a 16 amino acid sequence which is almost identical to the CaM binding domain and protein kinase C phosphorylation site of neuromodulin. Neurogranin is dentritic specific and neuromodulin is concentrated in axonal growth cone membranes where it is transported by rapid axonal transport. Neuromodulin is one of only a limited number of proteins whose synthesis is specifically increased during axonal elongation. There is evidence that neuromodulin is attached to membranes by palmitylated cysteine residues near the N-terminus. We have discovered that protein kinase C (PKC) phosphorylation abolishes the binding of CaM to neuromodulin, and we propose that neuromodulin and neurogranin may function to localize CaM at specific sites in neurons and release free CaM in response to PKC phosphorylations. The general goals of this proposal are to test our hypotheses that phosphorylations of neuromodulin or neurogranin may control their interactions with CaM in vitro and in vivo. Specific objectives of this proposal are to quantitate neurogranin/ CaM interactions, determine if the levels of free CaM are regulated by PKC catalyzed phosphorylation of neuromodulin or neurogranin in vivo , determine if these proteins will inhibit CaM stimulation of CaM regulated enzymes, determine if neuromodulin interacts with components of the membrane cytoskeleton, and to develop an in vitro assay for palmitylation of neuromodulin.
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