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 receptor-current response of the neuron to brief and prolonged odorant exposure and is able to produce the adaptation observed under repeated or sustained stimulation.

Fig. 1.

Model predictions for stimulation of an ORN with a 1-s odorant pulse of various concentrations as in figure 2A of ref. . (A) Simulated receptor currents associated with exposure to 5 (yellow), 10 (purple), 20 (cyan), 50 (red), 100 (green), or 300 (blue) μM cineole, compared with current traces obtained from the experimental data of Reisert and Matthews (30) (black curves). [Black current traces in the image are reprinted with permission from ref. (Copyright 1999, Blackwell Publishing).] (B) Time courses for various quantities in the model as follows: aG, active G-proteins; Ca, intracellular free Ca²⁺; CaCaM, Ca²⁺-associated calmodulin; aCaMK, active CaMK; IX, intermediate Ca²⁺-stimulated substance; V, membrane potential; CNG current; and Cl(Ca) current. The variable bLR (proportion of ligand-bound receptors) is not depicted because its time course closely resembles that of aG. Color coding is the same as in A.

Fig. 2.

Model predictions for the step-pulse adaptation experiment in figure 5 A–D of ref. . (A) Simulated receptor currents associated with a 4-s exposure to 0 (blue), 2 (green), 5 (red), or 10 (cyan) μM odorant, followed by a 1-s 20 μM test-pulse; black traces were obtained from the experimental data of Reisert and Matthews (30). [Black current traces in the image are reprinted with permission from ref. (Copyright 1999, Blackwell Publishing).] All currents have been normalized to the peak amplitude evoked by a 300 μM stimulus. (B) Time courses for various quantities in the model (same as in Fig. 1).

Fig. 3.

Model predictions for the exposure of a frog ORN to 100 μM odorant for 60 s as in figure 7A of ref. . (A) Simulated receptor current (blue) compared with filtered data from the experiments of Reisert and Matthews (16) (black trace). [Black current trace in the image is reprinted with permission from ref. (Copyright 2001, Blackwell Publishing).] (B) Time courses for various quantities in the model (same as in Fig. 1).