TY  - JOUR
AU  - Bruce, Neil J.
AU  - Narzi, Daniele
AU  - Trpevski, Daniel
AU  - van Keulen, Siri C.
AU  - Nair, Anu G.
AU  - Röthlisberger, Ursula
AU  - Wade, Rebecca C.
AU  - Carloni, Paolo
AU  - Hellgren Kotaleski, Jeanette
TI  - Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
JO  - PLoS Computational Biology
VL  - 15
IS  - 10
SN  - 1553-7358
CY  - San Francisco, Calif.
PB  - Public Library of Science
M1  - FZJ-2019-05318
SP  - e1007382 -
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31665146
UR  - <Go to ISI:>//WOS:000500776600040
DO  - DOI:10.1371/journal.pcbi.1007382
UR  - https://juser.fz-juelich.de/record/866099
ER  -