BioModels

Calmodulin sits at the center of molecular mechanisms underlying learning and memory. Its complex, and sometimes opposite, influences via the binding to various proteins are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favoring Long-term-potentiation (LTP) or depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interaction with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, neurogranin limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, neurogranin synchronizes the opening of calmodulin's two lobes and promotes their activation at specific frequencies, increasing the chance of CaMKII trans-autophosphorylation. Importantly, the positive effect of neurogranin on CaMKII activation is mediated via CaN, and too few or too much CaN will abolish this effect. Furthermore, the amount of neurogranin itself differentially regulates the levels of CaN and CaMKII activities, as well as the frequencies at which the balance switch from one to the other.

• Neurogranin Stimulates Ca2+/calmodulin-dependent Kinase II by Inhibiting Calcineurin at Specific Calcium Spike Frequencies
• Lu Li, Massimo Lai, Stephen Cole, Nicolas Le Novère, Stuart J. Edelstein
• PLOS Computational Biology , 12/ 2019 , DOI: 10.1101/597278
Affiliation: Babraham Institute, Cambridge, United Kingdom Quantitative Systems Pharmacology, CERTARA, Canterbury, United Kingdom Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom aSciStance Ltd, Cambridge, United Kingdom Scipio bioscience, Paris, France
Abstract: Calmodulin sits at the centre of molecular mechanisms underlying learning and memory. Its complex, and sometimes opposite influences, via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favouring Long-term potentiation (LTP) or depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interaction with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, neurogranin limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies, increasing the chance of CaMKII trans-autophosphorylation. Taken together, our study reveals dynamic regulatory roles played by neurogranin on synaptic plasticity, which provide mechanistic explanations to opposing experimental findings.