Neurogranin provides a kinetic proof reading mechanism for decoding Ca2+signals that may govern the induction of synaptic plasticity
© Kubota and Waxham; licensee BioMed Central Ltd. 2008
Published: 11 July 2008
At excitatory synapses of hippocampal CA1 pyramidal neurons, the activation of postsynaptic calcium/calmodulin-dependent protein kinase II (CaMKII) by calmodulin (CaM) during a brief high magnitude elevation of intracellular Ca2+ concentration ([Ca2+]i) results in LTP induction. Conversely, the same protein, CaM, activates PP2B (calcineurin) during a prolonged modest rise of [Ca2+]i that induces LTD [1, 2]. We would like to understand the mechanism by which the same protein (CaM) can activate one process while suppressing the other?
One possible candidate protein with the potential to regulate CaM distribution among its targets is neurogranin (Ng or also called RC3). Ng is a 78 amino acid neuronal protein enriched in CA1 pyramidal neurons that interacts with the C-terminal lobe of CaM both in the presence and absence of Ca2+ . Interestingly, the N-terminal lobe of CaM binds dephospho-CaMKII tighter than the C-terminal lobe and Ng accelerates the Ca2+ dissociation from the C-terminal lobe of CaM in the presence of CaMKII . The dissociation of Ca2+ promotes the dissociation of CaM from its target. However, once autophosphorylated at Thr286, CaMKII becomes resistant to the action of Ng and binds CaM with much higher affinity than PP2B [3, 4]. Lastly, an extended exposure of Thr286-phosphorylated CaMKII to lower Ca2+ concentrations leads to a slow CaM dissociation followed by an inhibitory phosphorylation at Thr305/306, which in turn prevents the rebinding of CaM to CaMKII . This inhibitory phosphorylation may a mechanism to prevent (unintended) LTP induction through a stochastic and accidental autophosphorylation of CaMKII.
Here we use a simple but realistic mathematical model constructed on experimental data of Ca2+-CaM-Ng-CaMKII interactions and investigate the potential kinetic proof reading mechanism underlying the induction of synaptic plasticity in CA1 pyramidal neurons [6, 7]. We specifically test if the kinetic mechanism described above and the simulated pattern/dynamics of Ca2+ dependent PP2B/CaMKII activation is consistent with the reported induction protocols of synaptic plasticity, especially with that of the synaptic timing dependent plasticity (STDP). We also examine the role of Ng using experimental data of Ng knockout animals . These simulation results support the idea that Ng serves as a kinetic barrier of CaMKII activation and proofreads Ca2+ transients during induction of plasticity.
- Yang SN, Tang YG, Zucker RS: Selective induction of LTP and LTD by postsynaptic [Ca]i elevation. J Neurophysiol. 1999, 81: 781-787.PubMedGoogle Scholar
- Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham NM: An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature. 1989, 340: 554-557. 10.1038/340554a0.View ArticlePubMedGoogle Scholar
- Gaertner TR, Putkey JA, Waxham MN: RC3/Neurogranin and Ca2+/calmodulin-dependent protein kinase II produce opposing effects on the affinity of calmodulin for calcium. J Biol Chem. 2004, 279: 39374-39382. 10.1074/jbc.M405352200.View ArticlePubMedGoogle Scholar
- Quintana AR, Wang D, Forbes JE, Waxham NM: Kinetics of calmodulin binding to calcineurin. Biochem Biophys Res Commun. 2005, 334: 674-680. 10.1016/j.bbrc.2005.06.152.View ArticlePubMedGoogle Scholar
- Hudmon A, Schulman H: Neuronal Ca2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Ann Rev Biochem. 2002, 71: 473-510. 10.1146/annurev.biochem.71.110601.135410.View ArticlePubMedGoogle Scholar
- Kubota Y, Putkey JA, Waxham MN: Neurogranin controls the spatiotemporal pattern of postsynaptic Ca2+/CaM signaling. Biophys J. 93: 3848-3859. 10.1529/biophysj.107.106849.Google Scholar
- Kubota Y, Putkey JA, Shouval HZ, Waxham MN: IQ-motif proteins influences intracellular free Ca2+ in hippocampal neurons through their interactions with calmodulin. J Neurophysiol. 99: 264-276. 10.1152/jn.00876.2007.Google Scholar
- Huang KP, Huang FL, Jager T, Li J, Reymann KG, Balschun D: Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci. 2004, 24: 10660-10669. 10.1523/JNEUROSCI.2213-04.2004.View ArticlePubMedGoogle Scholar
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