Journal Article

FZJ-2019-05318

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

Bruce, N. J. ; Narzi, D. ; Trpevski, D. ; van Keulen, S. C. ; Nair, A. G. ; Röthlisberger, U. ; Wade, R. C. (Corresponding author) ; Carloni, P. (Corresponding author)FZJ* ; Hellgren Kotaleski, J. (Corresponding author)

2019
Public Library of Science San Francisco, Calif.

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Please use a persistent id in citations: http://hdl.handle.net/2128/23211  doi:10.1371/journal.pcbi.1007382

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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)

Appears in the scientific report 2019

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