Computational model of the cAMP-mediated sensory response and calcium-dependent adaptation in vertebrate olfactory receptor neurons

Abstract

We develop a mechanistic mathematical model of the G-protein coupled signaling pathway responsible for generating current responses in frog olfactory receptor neurons. The model incorporates descriptions of ligand-receptor interaction, intracellular transduction events involving the second messenger cAMP, effector ion-channel activity, and calcium-mediated feedback steps. We parameterized the model with respect to suction pipette current recordings from single cells stimulated with multiple odor concentrations. The proposed model accurately predicts the receptorcurrent response of the neuron to brief and prolonged odorant exposure and is able to produce the adaptation observed under repeated or sustained stimulation.mathematical model ͉ receptor neuron ͉ olfaction ͉ signal transduction ͉ cilia S ensory transduction of odors occurs in olfactory receptor neurons (ORNs) located in the olfactory epithelium of vertebrates and the antennal structures of invertebrates (1). The first step in transduction is the binding of an odorant molecule to a seven-transmembrane-domain receptor protein in the cilia of an ORN. This interaction triggers a G-protein-coupled cascade that activates the enzyme adenylyl cyclase, resulting in an increase in intraciliary adenosine-3Ј,5Ј-cyclic monophosphate (cAMP). When cAMP increases, it opens cyclic nucleotidegated (CNG) channels, allowing calcium and other extracellular cations into the cilia and generating an inward current. Elevated Ca 2ϩ levels in the cilia activate Ca 2ϩ -gated chloride [Cl(Ca)] channels, creating an outward flow of Cl Ϫ ions and producing amplification of the inward current (2-4) that results in membrane depolarization and the generation of action potentials in the cell soma (5). This increase in intracellular calcium initiates termination and adaptation of the cell's response by means of deactivation and feedback mechanisms, including interactions mediated by Ca 2ϩ -calmodulin (CaCaM) and Ca 2ϩ ͞calmodulin-kinase II (CaMK) (6-10). The Cl(Ca) channels remain open until enough calcium is extruded from the cilia via the Na͞Ca exchanger (NCX) (11).After stimulation, an ORNЈs response to subsequent stimuli becomes attenuated. Short-term adaptation is observed as a decrease in responsiveness to odor presentations that occur within a few seconds after a brief stimulus (7); it may be mediated in part by CaCaM inhibition of the CNG channel (12). Desensitization occurs when an odor is experienced for a sustained interval of at least several seconds: the ORNЈs response declines while the stimulus continues to be present (13,14). In this case, several aspects of the response to a subsequent stimulus are altered, including a decrease in the slope of the rising phase, as well as an increase in the speed of decay, of the stimulus-induced inward current (7, 13). Experiments (15) have demonstrated that the molecular mechanisms responsible for desensitization are likely to act upstream of cAMP production; inhibition of adenylyl cyclase activity by CaMK is a possible mechanism (13). L...

Modeling of the receptor, G-protein and effector reactions in vertebrate olfactory receptor neurons

“…The models were made compatible by minimizing the difference in cAMP production rate when ignoring post effector inhibitory mechanisms. When our RGE model replaced the RGE-part of [2] (through the cAMP synthesis equation), the output from the combined model closely reproduced the output from the original model [2] at six different (pulse) stimulus intensities. Our model complements and extends the previous model [2] with a more elaborate treatment of the initial RGE-processes.…”

“…The new RGE-model was integrated-and linked to a previous model of receptor potential generation in vertebrate ORNs. [2], which had a specific emphasis on biochemical reactions following the effector enzyme. The models were made compatible by minimizing the difference in cAMP production rate when ignoring post effector inhibitory mechanisms.…”

“…Since our aim was to develop a model for vertebrate ORNs, certain parts of the previous model were reinterpreted. Biologically realistic values for the rate parameters and initial densities of reacting species were estimated by calibrating the model to empirical data for vertebrates [2,3]. The new RGE-model was integrated-and linked to a previous model of receptor potential generation in vertebrate ORNs.…”

Olfactory Cell-Based Smell Sensors

“…When large amounts of Ca 2+ accumulate in the cilium, Ca 2+ -gates chloride [Cl(Ca)] channels were activated, creating an outward flow of Cl − ions and amplifying the inward current that results in membrane depolarization and the generation of action potentials in the cell soma. The Cl(Ca) channels remain open until enough calcium is extruded from the cilia via the Na/Ca exchanger (NCX) [18,19]. After odor stimulation, ions flow in and out of the membrane causing ion channel currents which can be modeled as the following:…”

Crosstalk between G-protein and Ca2+ pathways switches intracellularcAMP levels

“…Previous mathematical modelling studies have largely focused on the separate effects of either G-protein or Ca 2+ signals on cAMP production. 4,[31][32][33][34][35][36] We aimed here to develop a model to include the effects of AC regulation by both Ca 2+ and G-protein dependent signals and thus to elucidate the interplay between these two major pathways modulating AC, and hence cAMP, concentrations within the framework of the network shown in Fig. 1.…”