Receptor Desensitization and Down-Regulation

Receptor down-regulation describes a slower, more prolonged process in which the actual number of available receptors is diminished.30,33 Although the exact mechanisms responsible for down-regulation are not fully understood, it appears that prolonged exposure of the agonist causes increased receptor removal, decreased receptor synthesis, or a combination of 

FIGURE 4-6 V Receptor regulation. Functionally active receptor sites are represented by an X Increased stimulation results in a decrease in receptor numbers (desensitization/down-regulatiorf), while decreased stimulation causes increased receptor numbers Csupersensitivity). 

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Grewal JS, Luttrell LM, Raymond JR. G Protein-coupled receptors desensitize and down-regulate epidermal growth factor receptors in renal mesangial cells. J Biol Chem 2001 276 27,335-27,344. 

Due to the lag time in therapeutic effect, it is thought that tricyclics manifest their true clinical effects by down regulation of beta receptors in the limbic system. With increased concentrations in synaptic norepinephrine, over a period of time the receptors desensitize and down regulate. 

Levin MC, Marullo S, Muntaner O, Andersson B, Magnusson Y. The myocardium-protective Gly-49 variant of the P,-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem 2002 277 30,429-30,435. 

Whether or not neurotransmitter receptors are abnormal in depression, the neurotransmitter receptor hypothesis of antidepressant action proposes that antidepressants, no matter what their initial actions on receptors and enzymes, eventually cause a desensitization, or down regulation, of key neurotransmitter receptors in a time course consistent with the delayed onset of antidepressant action of these drugs (Figs. 6—1 through 6—6). 

Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F, Martini C (2002) A3 adenosine receptors in human astrocytoma cells agonist-mediated desensitization, internalization, and down-regulation. Mol Pharmacol... 

Administration of multiple daily doses of drug produces down-regulation faster than single daily dosing and allows a lower dose per injection.6.29 in a time course study in rats, DMI (10 mg/kg b.i.d.) elicited maximal desensitization of cAMP accumulation by isoproterenol in cortical slices in 5 to 7 days and down-regulation of P-adrenoceptors in cortical membranes after 7 days. After DMI withdrawal, the subsensitive NE receptors returned to normal within a week.6 After multiple ECS treatments, P-adrenoceptors remain down-regulated for at least a... 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Receptor desensitization, internalization, and/or down-regulation may play a role in the development of tolerance to opioid receptor agonists (Clark et al. 

Millar, J.B., and Rozengur, E. (1990) Chronic desensitization to bombesin by progressive down-regulation of bombesin receptors in Swiss 3T3 cells./. Biol. Chem. 265, 12052-12058. 

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