Abstract
Frequently, a common chemical entity triggers opposite cellular processes, which implies that the components of signalling networks must detect signals not only through their chemical natures, but also through their dynamic properties. To gain insights on the mechanisms of discrimination of the dynamic properties of cellular signals, we developed a computational stochastic model and investigated how three calcium ion (Ca2+)-dependent enzymes (adenylyl cyclase (AC), phosphodiesterase 1 (PDE1), and calcineurin (CaN)) differentially detect Ca2+ transients in a hippocampal dendritic spine. The balance among AC, PDE1 and CaN might determine the occurrence of opposite Ca2+-induced forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). CaN is essential for LTD. AC and PDE1 regulate, indirectly, protein kinase A, which counteracts CaN during LTP. Stimulations of AC, PDE1 and CaN with artificial and physiological Ca2+ signals demonstrated that AC and CaN have Ca2+ requirements modulated dynamically by different properties of the signals used to stimulate them, because their interactions with Ca2+ often occur under kinetic control. Contrarily, PDE1 responds to the immediate amplitude of different Ca2+ transients and usually with the same Ca2+ requirements observed under steady state. Therefore, AC, PDE1 and CaN decode different dynamic properties of Ca2+ signals.
Highlights
With the expansion of our knowledge on cell signalling, it became evident that signal transduction emerges from the combination of highly interconnected networks often formed by signalling pathways with opposing actions, but activated by the same signal[1]
The best characterized forms of long-term potentiation (LTP) and long-term depression (LTD) occur in the synapses between CA3 and CA1 hippocampal pyramidal neurons and require the activation of NMDA receptors (NMDARs), which promotes the influx of calcium ions (Ca2+) to the cytosol[1,4]
We developed a computational model of a single hippocampal spine, the cellular compartment where the glutamatergic postsynaptic machinery is located[15]
Summary
With the expansion of our knowledge on cell signalling, it became evident that signal transduction emerges from the combination of highly interconnected networks often formed by signalling pathways with opposing actions, but activated by the same signal[1]. Among the processes that are likely to be regulated by dynamic characteristics of input signals are the long-term forms of synaptic plasticity. It is generally accepted that the direction of the synaptic alteration, depression or potentiation, is determined by the relationship between the Ca2+ affinities of the molecules implicated with each type of plasticity and the magnitude of the [Ca2+] rise. Calcineurin (CaN) is the only phosphatase involved with plasticity activated by Ca2+ in its free form and complexed with calmodulin (Ca2+/CaM)[6]. To counteract the activity of AC, a specific phosphodiesterase, PDE1A2 (referred as PDE1 in the remaining of the paper), the enzyme that hydrolyses cAMP, is highly concentrated in the brain and is regulated by binding to Ca2+/CaM8
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
