title: Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling.
abstract: In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng-/- mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng+/+ mice, the frequency-response curve of Ng-/- shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng-/- slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+ ([Ca2+]i) response in Ng+/+ compared with Ng-/- mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng-/- mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+]i by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+]i at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.
authors.affiliation: Section on Metabolic Regulation, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510, USA. kphuang@helix.nih.gov
authors.forename: Kuo-Ping
authors.initials: KP
authors.lastname: Huang
authors.forename: Freesia L
authors.initials: FL
authors.lastname: Huang
authors.forename: Tino
authors.initials: T
authors.lastname: Jäger
authors.forename: Junfa
authors.initials: J
authors.lastname: Li
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Reymann
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051579:Neurogranin; D013037:Spatial Behavior / Q000502:physiology
chemical_list: D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; D051579:Neurogranin; D002118:Calcium