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

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 regula...

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Autores principales: Bruce, Neil J., Narzi, Daniele, Trpevski, Daniel, van Keulen, Siri C., Nair, Anu G., Röthlisberger, Ursula, Wade, Rebecca C., Carloni, Paolo, Hellgren Kotaleski, Jeanette
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821081/
https://www.ncbi.nlm.nih.gov/pubmed/31665146
http://dx.doi.org/10.1371/journal.pcbi.1007382
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author Bruce, Neil J.
Narzi, Daniele
Trpevski, Daniel
van Keulen, Siri C.
Nair, Anu G.
Röthlisberger, Ursula
Wade, Rebecca C.
Carloni, Paolo
Hellgren Kotaleski, Jeanette
author_facet Bruce, Neil J.
Narzi, Daniele
Trpevski, Daniel
van Keulen, Siri C.
Nair, Anu G.
Röthlisberger, Ursula
Wade, Rebecca C.
Carloni, Paolo
Hellgren Kotaleski, Jeanette
author_sort Bruce, Neil J.
collection PubMed
description 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 Gα(olf) and inhibitory Gα(i) 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 Gα(olf) and Gα(i) 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.
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spelling pubmed-68210812019-11-08 Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals Bruce, Neil J. Narzi, Daniele Trpevski, Daniel van Keulen, Siri C. Nair, Anu G. Röthlisberger, Ursula Wade, Rebecca C. Carloni, Paolo Hellgren Kotaleski, Jeanette PLoS Comput Biol Research Article 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 Gα(olf) and inhibitory Gα(i) 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 Gα(olf) and Gα(i) 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. Public Library of Science 2019-10-30 /pmc/articles/PMC6821081/ /pubmed/31665146 http://dx.doi.org/10.1371/journal.pcbi.1007382 Text en © 2019 Bruce et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bruce, Neil J.
Narzi, Daniele
Trpevski, Daniel
van Keulen, Siri C.
Nair, Anu G.
Röthlisberger, Ursula
Wade, Rebecca C.
Carloni, Paolo
Hellgren Kotaleski, Jeanette
Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title_full Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title_fullStr Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title_full_unstemmed Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title_short Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
title_sort regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821081/
https://www.ncbi.nlm.nih.gov/pubmed/31665146
http://dx.doi.org/10.1371/journal.pcbi.1007382
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