RC3 NEUROGRANIN, A POSTSYNAPTIC CALPACITIN FOR SETTING THE RESPONSE THRESHOLD TO CALCIUM INFLUXES/

In this review, we attempt to cover the descriptive, biochemical and m olecular biological work that has contributed to our current knowledge about RC3/neurogranin function and its role in dendritic spine develo pment, long-term potentiation, long-term depression, learning, and mem ory. Based on the data reviewed here, we propose that RC3, GAP-43, and the small cerebellum-enriched peptide, PEP-19, belong to a protein fa mily that we have named the calpacitins. Membership in this family is based on sequence homology and, we believe, a common biochemical funct ion. We propose a model wherein RC3 and GAP-43 regulate calmodulin ava ilability in dendritic spines and axons, respectively, and calmodulin regulates their ability to amplify the mobilization of Ca2+ in respons e to metabotropic glutamate receptor stimulation. PEP-19 may serve a s imilar function in the cerebellum, although biochemical characterizati on of this molecule has lagged behind that of RC3 and GAP-43. We sugge st that these molecules release CaM rapidly in response to large influ xes of Ca2+ and slowly in response to small increases. This nonlinear response is analogous to the behavior of a capacitor, hence the name c alpacitin. Since CaM regulates the ability of RC3 to amplify the effec ts of metabotropic glutamate receptor agonists, this activity must, ne cessarily, exhibit nonlinear kinetics as well. The capacitance of the system is regulated by phosphorylation by protein kinase C, which abro gates interactions between calmodulin and RC3 or GAP-43. We further pr opose that the ratio of phosphorylated to unphosphorylated RC3 determi nes the sliding LTP/LTD threshold in concert with Ca2+/ calmodulin-dep endent kinase II. Finally, we suggest that the close association betwe en RC3 and a subset of mitochondria serves to couple energy production with the synthetic events that accompany dendritic spine development and remodeling.