Regulation of receptor number

Milligan, G. and Bond, R.A. (1997) Inverse agonism and regulation of receptor number. Trends Pharmacol. Sci. 18 468-474. 

Gallon VA. Putative nuclear triiodothyronine receptors in tadpole erythrocytes regulation of receptor number by thyroid hormone. Endocrinology 1984 114 735-742. 

While receptor function is regulated rapidly (over seconds or minutes), regulation of receptor number takes much longer, commonly many hours. In isolated cells it is often maximal only 24 h of continuous agonist exposure (Danner and Lohse 1999). Changes in P-adrenergic receptor number can be effected by two classes of mechanisms ... 

The regulation of receptor synthesis is a second component of receptor downregulation. It involves processes that reduce gene transcription, mRNA stability, and receptor half-life time. It should be noted that mechanisms in addition to the regulation of the receptor number may account for tolerance development. Second messenger levels and enzyme activities that participate in the signaling of a given receptor are... 

Gene regulation by tocopherols has mainly been associated with PKC because of its deactivation by a-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, API). A direct participation of the pregnane X receptor (PXR)/ retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element appear in some cases to be implicated as well. The obser ved immunmodulatory function of a-tocopherol may also be attributed to the fact that the release of the proinflammatory cytokine interlukin-l 3 can be inhibited by a-tocopherol via... 

Abrupt interruption of propranolol therapy in individuals with angina pectoris has been associated with reappearance of angina, acute myocardial infarction, or death due to a sudden increase in sympathetic nervous system tone to the heart. The mechanisms underlying these reactions are unknown, but they may be the result of an increase in the number of p-receptors that occur following chronic p-adrenoceptor blockade (up-regulation of receptors). When it is advisable to discontinue propranolol administration, such as before coronary bypass surgery, the dosage should be tapered over 2 to 3 days. 

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. 

The antidepressants, generally, produce their therapeutic effects by blocking the reuptake of one or more catecholamines (norepinephrine, serotonin, and dopamine), which leads to a decrease (down-regulation) of the number of post-synaptic receptors—generally within seven to twenty-one days, coinciding with the onset of clinical effect (see chapter 3). The MAOIs block monoamine oxidase, which metabolizes the catecholamines stored at the nerve ending of the presynaptic neuron—thereby making more catecholamine available. Stimulants increase the release of catecholamines. Buspirone is a 5-HT lA receptor blocker. 

The majority of Type-II diabetics are obese (II b) and suffer predominantly from an impairment of insulin action due to heterogeneous mechanisms. Decreased insulin responsiveness of peripheral tissues may be due to (1) a post-receptor defect with secondary hyperinsulinaemia, (2) down-regulation of the number of insulin receptors, or (3) the glucotoxic effect of hyper-glycaemia caused by accelerated hepatic glucose production. An additional impairment of insulin secretion is present, however, only in non-obese Type-II-a diabetics. 

Hormones themselves are important regulators of the number of receptors in a cell this regulation may be homologous or heterologous. 

It has been known since the work of Rona et al. (1959) that sympathomimetic amines at dose levels, which would be lethal for humans produce extensive necrosis in the rat myocardium. The lesions and those produced in the same species by hypoxia have morphological features in common (Niles et al. 1968). A proteolipid binding H-isoprenaline was localized in the plasma membrane of the feline heart ventricular myocytes (Ochoa et al. 1972). Exposing myocytes to catecholamines lead to down-regulation of the number of receptors within minutes (Linden et al. 1984). 

The responsiveness of a tissue to a hormone depends on the density of receptors within its component cells. The number of receptors is determined by their rate of synthesis and catabolism, which is itself controlled by complex feedback mechanisms involving hormone action. Some chemicals are known to interfere with this regulation. For example, TCDD can act to increase or decrease the expression of the oestrogen receptor. ... 

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