Antagonists down-regulation

Prolonged exposure of -adrenoceptor agonists down-regulates -adrenoceptors, ie, their number decreases and they become less responsive. On the other hand, prolonged exposure to -adrenoceptor antagonists (those without ISA) upregulates -adrenoceptors, ie, their numbers increase and they become more responsive. Therefore, patients on -adrenoceptor blocker therapy should be withdrawn from this medication gradually (40). 

Whitman, S.P., Civoh, R, and Daniel, L.W., 1997, Protein kinase Cpil activation by 1-P-D-arabino-furanosylcytosine is antagonistic to stimulation of apoptosis and BCL-2a down-regulation. J. Biol. Chem. 272 23481-23484... 

Memo M, Bovolin P, Costa E, Grayson DR. 1991. Antagonists of the NMDA sensitive glutamate receptor down regulate mRNAs encoding various GABA receptors in cerebellar granule neurons. Mol Pharmacol 39 599-603. 

Whitman SP, Civoli F, Daniel LW (1997) Protein kinase Cbetall activation by 1-beta-D-arabinofiiranosylcytosine is antagonistic to stimulation of apoptosis and Bcl-2alpha down-regulation. J Biol Chem 272 23481-2384... 

Buspirone acts as an agonist of somatodendritic 5-HTja autoreceptors, and has variable antagonistic effects on postsynaptic 5-HTja receptors (Jann, 1988 Baldessarini, 1996 Chouinard et ah, 1999). It also causes down-regulation of d-HTj receptors (Cole and Yonkers, 1995). 

Paudice P, Raiteri M Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens. Br J Pharmacol 103 1790-1794, 1991 Paul lA, Trullas R, Skolnick P, et al Down-regulation of cortical (3-adrenoceptors by chronic treatment with functional NMDA antagonists. Psychopharmacology 106 285-287, 1992... 

Considerable attention has been paid to the ultimate postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, cAMP concentrations have consistently decreased rather than increased, in spite of the presumably longer duration of action of the transmitters. In addition, the number of postsynaptic -adrenoceptors has shown a measurable decrease that follows the same delayed time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of receptors. Decreases in norepinephrine-stimulated cAMP and in B-adrenoceptor binding have been conclusively shown for selective norepinephrine uptake inhibitors, those with mixed action on norepinephrine and serotonin, monoamine oxidase inhibitors, and even electroconvulsive therapy. Such changes do not consistently occur after the selective serotonin uptake inhibitors, 2 receptor antagonists, and mixed serotonin antagonists. 

Early exploration of derivatives of the natural estrogens failed to provide the necessary tissue selectivity, but an example of successful application of the steroid-like scaffold was realized with fulvestrant (10), which has been used in breast cancer therapy since the early 2000s. Fulvestrant (10) is a full ER antagonist that displays no agonistic effects, and it works both by down-regulating and by degrading the ER.1,19,20... 

Here we provide the basic methods we use to study chemokine-receptor trafficking. These methods have been used in conjunction with chemokines and chemokine antagonists, and with other agents (e.g., phorbol esters) that can induce receptor endocytosis. In the following protocols, we refer only to the use of chemokines. We use the operational terms endocytosis and recycling to avoid alternative expressions such as down-modulation or down-regulation, desensitization, and resensitization, which may be used to reflect the functional state of the receptor or cell. 

Trazodone (SEDA-7,19-21) is a triazolopyridine derivative that selectively but weakly inhibits 5-hydroxytrypta-mine (5-HT) re-uptake and is an alpha-adrenoceptor antagonist at both presynaptic and postsynaptic receptors (1). During long-term administration it down-regulates serotonin receptors (2). 

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