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

Authors: Neil J. Bruce1*, Daniele Narzi2*, Daniel Trpevski3*, Siri Camee van Keulen2,4*, Anu G. Nair10, Ursula Roethlisberger2, Rebecca C. Wade1,5,6, Paolo Carloni7,8, and Jeanette Hellgren Kotaleski3,9

Author information: 1 Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany. 2 Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland 3 Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 10044, Stockholm, Sweden. 4 Department of Computer Science, Stanford University, Stanford, California 94305, USA 5 Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany 6 Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany 7 Department of Physics and Department of Neurobiology, RWTH Aachen University, 52078 Aachen, Germany 8 Institute for Neuroscience and Medicine (INM)-11, Forschungszentrum Jülich, 52428 Jülich, Germany, Institute of Neuroscience and Medicine (INM-9) and Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, Wilhelm-Johnen-Strasse, 52425 Jülich, Germany 9 Department of Neuroscience, Karolinska Institutet, 17177, Solna, Sweden. 10 Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

* Joint first authors

Corresponding authors: Jeanette Hellgren Kotaleski (, Paolo Carloni (, Rebecca C. Wade ( and Ursula Roethlisberger (

Journal: PLOS Computational Biology

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Citation: Bruce NJ, Narzi D, Trpevski D, van Keulen SC, Nair AG, Röthlisberger U, et al. (2019) Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals. PLoS Comput Biol 15(10): e1007382.


Licence: CC BY 4.0 International license


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.


Here you can find the data used and generated in this work, along with the model produced.