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

• DOI: 10.1371/journal.pcbi.1007382
• Publication Date: 2019-10-30T17:28:55Z
• Authors: Neil J. Bruce; Daniele Narzi; Daniel Trpevski; Siri C. van Keulen; Anu G. Nair; Ursula Röthlisberger; Rebecca C. Wade; Paolo Carloni; Jeanette Hellgren...
• Keywords: Cell biology; protein-protein association; QH301-705.5; Second messenger system; 610; Signal transduction; catalytic mechanism; Molecular Dynamics Simulation; Synaptic plasticity; Cellular and Molecular Neuroscience; 03 medical and health sciences; Inhibitory postsynaptic potential; Dogs; Modelling and Simulation; expression; Genetics; Adenylyl cyclase; Animals; Protein Isoforms; Biology (General); Biology; Molecular Biology; Ecology, Evolution, Behavior and Systematics; domains; info:eu-repo/classification/ddc/610; parameters; Neurons; 0303 health sciences; Neuronal Plasticity; Ecology; organization; Gi alpha subunit; simulation; Synapse; inhibition; Corpus Striatum; GTP-Binding Protein alpha Subunits; Rats; Kinetics; Computational Theory and Mathematics; receptor proteins; Long-term potentiation; dopamine; Ternary complex; Receptor; Research Article; Adenylyl Cyclases; Signal Transduction

Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor reinforcement learning. Strengthening the corticostriatal synapses depends on second messenger cAMP, whose synthesis catalysed by enzyme adenylyl cyclase 5 (AC5), which itself regulated stimulatory Gαolf inhibitory Gαi proteins. AC isoforms have been suggested act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close time. However, mechanism for this currently unclear, seems lie their diverse regulation patterns. Despite attempts isolate ternary complex, it not known if can bind AC5 simultaneously, nor what complex would have. Using protein structure-based molecular dynamics simulations, we show that stable inactive. These along with Brownian simulations estimate association rates constants, constrain kinetic model shows presence inactive crucial AC5's ability detect coincident signals, producing synergistic increase cAMP. results reveal some prerequisites plasticity, explain recent experimental data cAMP concentrations following receptor activation. Moreover, they provide insights into mechanisms control signal processing different isoforms.