% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Bruce:866099,
      author       = {Bruce, Neil J. and Narzi, Daniele and Trpevski, Daniel and
                      van Keulen, Siri C. and Nair, Anu G. and Röthlisberger,
                      Ursula and Wade, Rebecca C. and Carloni, Paolo and Hellgren
                      Kotaleski, Jeanette},
      title        = {{R}egulation of adenylyl cyclase 5 in striatal neurons
                      confers the ability to detect coincident neuromodulatory
                      signals},
      journal      = {PLoS Computational Biology},
      volume       = {15},
      number       = {10},
      issn         = {1553-7358},
      address      = {San Francisco, Calif.},
      publisher    = {Public Library of Science},
      reportid     = {FZJ-2019-05318},
      pages        = {e1007382 -},
      year         = {2019},
      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.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {574 - Theory, modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31665146},
      UT           = {WOS:000500776600040},
      doi          = {10.1371/journal.pcbi.1007382},
      url          = {https://juser.fz-juelich.de/record/866099},
}