Kinetic Model for the Activation of Mammalian Olfactory Receptor.

Abstract

The sense of smell is triggered by binding of odorants to a set of olfactory receptors (ORs), the activation of which generates specific patterns of neuronal signals in olfactory bulbs. Despite a long history of research and speculations, very little is known about the actual mechanism of OR activation. In particular, there is virtually no theoretical framework capable of describing the kinetics of olfactory activation at a quantitative level. Based on the fact that mammalian ORs belong to a class of G-protein coupled receptors (GPCRs) and utilizing the information available from recent studies on other types of GPCRs with known structural data, we construct a minimal kinetic model for mammalian olfactory activation, obtaining a new expression for the signal strength as a function of odorant and G-protein concentrations and defining this as odor activity (OA). The parametric dependence of OA on equilibrium dissociation and rate constants provides a new comprehensive means to describe how odorant-OR binding kinetics affects the odor signal, and offers new quantitative criteria for classifying agonistic, partially agonistic, and antagonistic (or inverse agonistic) behavior. The dependence of OA on the concentration of G-proteins also suggests a new experimental method to determine key equilibrium constants for odorant-OR and G-protein-OR association/dissociation processes.