Constitutive Receptor Activity

A basic principle of receptor theory is that when a receptor is activated by a ligand, the effect produced by the ligand is proportional to the concentration of the ligand, e.g., it follows the Law of Mass Action (20). It is now becoming apparent that receptors spontaneously form active complexes as a result of interactions with other proteins. This is especially true when receptor cDNA is expressed in cell systems such that the relative abundance of a receptor is in excess of that normally occur-

ring in the native state or associates with proteins that reflect the host cell milieu in which the receptor is expressed, rather than an intrinsic property of the receptor in its natural environment. This is a major issue in the characterization of ligand efficacy (49). A spontaneous interaction between receptor and effector can occur more frequently in a system where the proteins are in excess and where factors normally present that control such interactions are absent. This is shown graphically in Fig. 10.3, where constitutive activity is shown in the range of 0-50 and where the theoretical effects of inverse agonists, full and partial, are shown. A quiescent system that is more reflective of classical receptor theory shows a full agonist, partial agonist, and what is now defined as a neutral antagonist. Constitutive receptor activation has been described in terms of protein ensemble theory (23) and in terms of allosteric transition (25), where changes in receptor conformation can occur through random thermal events (42, 43) and may also be described in terms of chaos theory (36).

Figure 10.4. Pharmacological versus functional antagonism. In the top panel, neurotransmitter A is released from neuron A, directly interacting with neuron B to produce a functional response. Antagonist a blocks the effects of A, a direct pharmacological antagonism of the effects of A. In the bottom panel, neurotransmitter A is released from neuron A, directly interacting with neuron X, which in turn releases neurotransmitter X, which acts on cell Y to produce a functional response. Antagonist JB blocks the effects of X on cell Y, but in the absence of other data on the actions of antagonist j3, seems to block the functional effects of A because of the circuitry involved. Antagonist /3 thus acts as a functional antagonist.

Figure 10.4. Pharmacological versus functional antagonism. In the top panel, neurotransmitter A is released from neuron A, directly interacting with neuron B to produce a functional response. Antagonist a blocks the effects of A, a direct pharmacological antagonism of the effects of A. In the bottom panel, neurotransmitter A is released from neuron A, directly interacting with neuron X, which in turn releases neurotransmitter X, which acts on cell Y to produce a functional response. Antagonist JB blocks the effects of X on cell Y, but in the absence of other data on the actions of antagonist j3, seems to block the functional effects of A because of the circuitry involved. Antagonist /3 thus acts as a functional antagonist.

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