RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes.
In this review, we attempt to cover the descriptive, biochemical and molecular biological work that has contributed to our current knowledge about RC3/neurogranin function and its role in dendritic spine development, long-term potentiation, long-term depression, learning, and memory. Based on the data reviewed here, we propose that RC3, GAP-43, and the small cerebellum-enriched peptide, PEP-19, belong to a protein family that we have named the calpacitins. Membership in this family is based on sequence homology and, we believe, a common biochemical function. We propose a model wherein RC3 and GAP-43 regulate calmodulin availability in dendritic spines and axons, respectively, and calmodulin regulates their ability to amplify the mobilization of Ca2+ in response to metabotropic glutamate receptor stimulation. PEP-19 may serve a similar function in the cerebellum, although biochemical characterization of this molecule has lagged behind that of RC3 and GAP-43. We suggest that these molecules release CaM rapidly in response to large influxes of Ca2+ and slowly in response to small increases. This nonlinear response is analogous to the behavior of a capacitor, hence the name calpacitin. Since CaM regulates the ability of RC3 to amplify the effects of metabotropic glutamate receptor agonists, this activity must, necessarily, exhibit nonlinear kinetics as well. The capacitance of the system is regulated by phosphorylation by protein kinase C, which abrogates interactions between calmodulin and RC3 or GAP-43. We further propose that the ratio of phosphorylated to unphosphorylated RC3 determines the sliding LTP/LTD threshold in concept with Ca2+/ calmodulin-dependent kinase II. Finally, we suggest that the close association between RC3 and a subset of mitochondria serves to couple energy production with the synthetic events that accompany dendritic spine development and remodeling.
Gerendasy
D D
DD
Department of Molecular Biology, Scripps Research Institute.
Sutcliffe
J G
JG
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003409:Congenital Hypothyroidism / Q000209:etiology / Q000378:metabolism; D016384:Consensus Sequence; D003712:Dendrites / Q000378:metabolism; D019922:GAP-43 Protein / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007037:Hypothyroidism / Q000150:complications / Q000378:metabolism; D017136:Ion Transport; D007858:Learning / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D008969:Molecular Sequence Data; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D051579:Neurogranin; D009473:Neuronal Plasticity / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012892:Sleep Deprivation / Q000502:physiology; D014714:Vertebrates / Q000378:metabolism
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D019922:GAP-43 Protein; C496649:NRGN protein, human; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; C496651:Nrgn protein, rat; C489091:Pcp4 protein, mouse; C489090:Pcp4 protein, rat; D010743:Phospholipids; D018094:Receptors, Metabotropic Glutamate; C050394:PCP4 protein, human; D051579:Neurogranin; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases; D002118:Calcium