title: Mechanisms of regulation of olfactory transduction and adaptation in the olfactory cilium.
abstract: Olfactory adaptation is a fundamental process for the functioning of the olfactory system, but the underlying mechanisms regulating its occurrence in intact olfactory sensory neurons (OSNs) are not fully understood. In this work, we have combined stochastic computational modeling and a systematic pharmacological study of different signaling pathways to investigate their impact during short-term adaptation (STA). We used odorant stimulation and electroolfactogram (EOG) recordings of the olfactory epithelium treated with pharmacological blockers to study the molecular mechanisms regulating the occurrence of adaptation in OSNs. EOG responses to paired-pulses of odorants showed that inhibition of phosphodiesterases (PDEs) and phosphatases enhanced the levels of STA in the olfactory epithelium, and this effect was mimicked by blocking vesicle exocytosis and reduced by blocking cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and vesicle endocytosis. These results suggest that G-coupled receptors (GPCRs) cycling is involved with the occurrence of STA. To gain insights on the dynamical aspects of this process, we developed a stochastic computational model. The model consists of the olfactory transduction currents mediated by the cyclic nucleotide gated (CNG) channels and calcium ion (Ca(2+))-activated chloride (CAC) channels, and the dynamics of their respective ligands, cAMP and Ca(2+), and it simulates the EOG results obtained under different experimental conditions through changes in the amplitude and duration of cAMP and Ca(2+) response, two second messengers implicated with STA occurrence. The model reproduced the experimental data for each pharmacological treatment and provided a mechanistic explanation for the action of GPCR cycling in the levels of second messengers modulating the levels of STA. All together, these experimental and theoretical results indicate the existence of a mechanism of regulation of STA by signaling pathways that control GPCR cycling and tune the levels of second messengers in OSNs, and not only by CNG channel desensitization as previously thought.
authors.affiliation: Neurosciences Unit, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal; Laboratory of Neural Systems, Psychobiology Sector, Department of Psychology, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Antunes
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Neurosciences Unit, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Sebastião
authors.affiliation: Neurosciences Unit, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal; Center for Mathematics, Computation and Cognition, Federal University of ABC, São Bernardo do Campo, Brazil.
authors.forename: Fabio Marques
authors.initials: FM
authors.lastname: Simoes de Souza
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000222:Adaptation, Physiological; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002923:Cilia; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009812:Odorants; D009831:Olfactory Mucosa / Q000378:metabolism*; D018034:Olfactory Receptor Neurons / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D010727:Phosphoric Diester Hydrolases; D034281:Dynamins; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine