The Journal of Neuroscience, November 24, 2004, ():
Neurogranin/RC3 Enhances Long-Term Potentiation and Learning by Promoting Calcium-Mediated Signaling
J. Neurosci. Huang et al.
24: 10660
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Schematic representation of Ng’s role in the modulation of free Ca2+ and Ca2+/CaM. A rise in Ca2+, through NMDA receptors (NMDAR), voltage-gated calcium channels (VGCC), and metabotropic glutamate receptor (mGluR)-IP3 coupled release from intracellular Ca2+stores (ICSs), causes dissociation of the Ng/CaM complex to form Ca2+4/CaM. This reaction implies that at any given Ca2+ influx a higher level of Ng will result in a greater concentration of free [Ca2+]i. A high level of free [Ca2+]i, in turn, favors the stimulation of Ca2+-dependent PKCs, which phosphorylate Ng and activate adenylyl cyclases 2 and 7 (AC2/7) to increase cAMP. Following Ng phosphorylation by PKC or oxidation by NO, which leads to formation of intramolecular disulfide (Ng-S-S) or glutathionylation (Ng-S-S-G), the free Ng concentration will drop and favor the formation of Ca2+4/CaM. The phosphorylated Ng will further stimulate the release of Ca2+ from ICSs to increase free [Ca2+]i and facilitate the dissociation of CaM from the Ng/CaM complex to form Ca2+4/CaM. These combined effects result in a rapid rise in the Ca2+/CaM level, causing an activation of Ca2+/CaM-dependent CaMKII and adenylyl cyclases 1 and 8 (AC1/8) to overcome the activities of PP2B and cyclic nucleotide phosphodiesterases (PDE). Since the latter two enzymes have higher affinities for Ca2+/CaM than the former enzymes, a higher level of Ca2+-transients in the presence of Ng favors the rise of Ca2+/CaM to a high level to stimulate CaMKII and AC1/8. An increase in the local concentration of Ng by activity-dependent de novo synthesis would sensitize the neurons for long-lasting potentiation. The autophosphorylated CaMKII can phosphorylate and activate the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) (Derkach et al., 1999) and stabilize NMDAR at postsynaptic sites (Strack and Colbran, 1998; Leonard et al., 2002). High level of Ca2+/CaM also favors the activation of NO synthase (NOS), which generates NO to enhance the presynaptic transmitter release (Prast and Philippu, 2001) and depress the GABAA receptor function (Zarri et al., 1994; Wexler et al., 1998). Thus, Ng enhances synaptic efficacy by sensitizing Ca2+- and Ca2+/CaM-mediated signaling, which, on the other hand, is depressed in Ng null mutants.
