E10 Receptor-ligand kinetics

Topic

The membrane receptor—the same type of receptor previously described in the general context of chemical synapses—is activated by neurotransmitters, hormones, or drugs in accordance with the law of mass action: the free ligand (any of these three substances) binds reversibly to the free membrane receptor to form a ligand-receptor complex. The rate at which this complex forms and dissociates depends on two constants specific to the membrane receptor—an association constant and a dissociation constant—the ratio of which defines the system's affinity, summarized by the membrane receptor's dissociation constant.

At equilibrium, the fraction of membrane receptors occupied by the ligand follows a simple hyperbolic relationship with respect to the free ligand concentration: it rises rapidly at low concentrations and then levels off as nearly all membrane receptors become occupied. However, when cooperative binding occurs across multiple sites on the membrane receptor, this relationship ceases to be hyperbolic and becomes a sigmoidal Hill relationship, characterized by a Hill coefficient specific to the membrane receptor; the higher this Hill coefficient, the more abrupt the transition between empty and fully occupied membrane receptors.

At all times, the conservation of the total receptor population links the free and bound forms of the membrane receptor: the amount of free membrane receptor plus the amount of ligand-bound membrane receptor always sums to the total number of available membrane receptors.

Furthermore, many membrane receptors transition to a desensitized state following prolonged exposure to the ligand: even if ligand occupancy of the membrane receptor is sustained, the response generated by that receptor diminishes, precisely because the desensitized membrane receptor ceases to translate its occupancy into a full functional response. When two ligands compete for the same binding site on a membrane receptor, their kinetics become coupled through the pool of free membrane receptors they share: the more the free receptor is occupied by one type of ligand, the less free receptor remains available for the other. The functional response resulting from this competition is summarized, in each instance, by a dose-response curve that rises with the ligand dose, approaching—but never exceeding—a maximum response. Ultimately, it is this membrane receptor—with its specific affinity, potential cooperativity, capacity for desensitization, and behavior in the presence of competing ligands—that determines the final functional response to neurotransmitters, hormones, or drugs.

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