loading page

Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
  • +8
  • Neil J. Bruce,
  • Daniele Narzi,
  • Daniel Trpevski,
  • Siri Camee van Keulen,
  • Anu G. Nair,
  • Ursula Röthlisberger,
  • Rebecca C. Wade,
  • Paolo Carloni,
  • Jeanette Hellgren Kotaleski,
  • jeanette,
  • Neil Bruce
Neil J. Bruce
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
Daniele Narzi
Laboratory of Computational Chemistry and Biochemistry, Ecole polytechnique fédérale de Lausanne, Lausanne, Switzerland
Daniel Trpevski
Science for Life Laboratory, School of Electrical Engineering and Computer Science, Royal Institute of Technology, Stockholm, Sweden, School of Informatics, University of Edinburgh, United Kingdom
Author Profile
Siri Camee van Keulen
Department of Computer Science, Stanford University, United States
Anu G. Nair
Institute for Molecular Life Sciences, University of Zürich, Zürich, Switzerland
Ursula Röthlisberger
Laboratory of Computational Chemistry and Biochemistry, Ecole polytechnique fédérale de Lausanne, Lausanne, Switzerland
Rebecca C. Wade
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
Paolo Carloni
Department of Physics and Department of Neurobiology, RWTH Aachen University, Aachen, Germany, Institute of Neuroscience and Medicine (INM-9) and Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, Jülich, Germany, Institute for Neuroscience and Medicine (INM)-11, Forschungszentrum Jülich, Jülich, Germany
Jeanette Hellgren Kotaleski
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden, Science for Life Laboratory, School of Electrical Engineering and Computer Science, Royal Institute of Technology, Stockholm, Sweden
Neil Bruce
Author Profile

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.