Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

• Verfasst von: Bruce, Neil J. [VerfasserIn]
• Verfasst von: Wade, Rebecca C. [VerfasserIn]
• Titel: Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
• Verf.angabe: Neil J. Bruce, Daniele Narzi, Daniel Trpevski, Siri C. van Keulen, Anu G. Nair, Ursula Röthlisberger, Rebecca C. Wade, Paolo Carloni, Jeanette Hellgren Kotaleski
• E-Jahr: 2019
• Jahr: October 30, 2019
• Fussnoten: Gesehen am 11.11.2019
• Titel Quelle: Enthalten in: Public Library of SciencePLoS Computational Biology
• Ort Quelle: San Francisco, Calif. : Public Library of Science, 2005
• Jahr Quelle: 2019
• Band/Heft Quelle: 15(2019,10) Artikel-Nummer e1007382, 32 Seiten
• ISSN Quelle: 1553-7358
• DOI: doi:10.1371/journal.pcbi.1007382
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Biochemical simulations
• Sach-SW: Biophysical simulations
• Sach-SW: Enzyme regulation
• Sach-SW: Molecular dynamics
• Sach-SW: Signal transduction
• Sach-SW: Signaling networks
• Sach-SW: Simulation and modeling
• Sach-SW: Synapses
• K10plus-PPN: 1681564319

Abstract

Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor in reinforcement learning. Strengthening of the corticostriatal synapses depends on the second messenger cAMP, whose synthesis is catalysed by the enzyme adenylyl cyclase 5 (AC5), which is itself regulated by the stimulatory Gαolf and inhibitory Gαi proteins. AC isoforms have been suggested to act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close in time. However, the mechanism for this is currently unclear, and seems to lie in their diverse regulation patterns. Despite attempts to isolate the ternary complex, it is not known if Gαolf and Gαi can bind to AC5 simultaneously, nor what activity the complex would have. Using protein structure-based molecular dynamics simulations, we show that this complex is stable and inactive. These simulations, along with Brownian dynamics simulations to estimate protein association rates constants, constrain a kinetic model that shows that the presence of this ternary inactive complex is crucial for AC5’s ability to detect coincident signals, producing a synergistic increase in cAMP. These results reveal some of the prerequisites for corticostriatal synaptic plasticity, and explain recent experimental data on cAMP concentrations following receptor activation. Moreover, they provide insights into the regulatory mechanisms that control signal processing by different AC isoforms.