Down-regulation of receptors

Ubiquitin-Dependent Down-Regulation of Receptors in Mammalian Cells... 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

The down-regulation of receptors by endocytosis. The hormone-mediated loss of receptors is often referred to as down-regulation. Continuous activation of receptors by hormone often leads to patching, a clustering of receptors as if they were cross-linked. Endocytosis of the patches removes them from the cell surface. The endocytotic vesicles, sometimes called receptosomes, fuse with lysosomes, where the contents are degraded by the lysosomal enzymes. Receptosomes also may allow entry of receptors into other cell compartments, such as the nucleus, by fusing with these organelles. 

The new chemical affects the cell s DNA Here, it causes DOWN-REGULATION of receptors. 

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 mechanisms whereby GH and other factors modulate receptor levels is not known. In medium- or long-term experiments use of protein synthesis inhibitors usually blocks such modulation, suggesting that de novo synthesis of receptors may be required, although involvement of other short-lived proteins cannot be ruled out. Rapid increase in receptor levels probably does not require synthesis of new receptors, and may be achieved by insertion of receptors that were previously stored in-tracellulqrly into the plasma membrane, and/or by activation of receptor proteins already in the plasma membrane in an inactive form. Down-regulation of receptors probably involves endocytosis, possibly followed by degradation [18]. 

More recently, monoclonal antibodies to the rabbit prolactin receptor have been described [49,50]. These showed strong species specificity, competed with 125I-la-belled prolactin for binding to receptors, and provided evidence for receptor heterogeneity in some tissues [49], Two of the monoclonal antibodies could block the actions of prolactin on casein synthesis in rabbit mammary gland explants, and one of them could inhibit milk production in vivo [50]. A third antibody could mimic the actions of prolactin on both casein and DNA synthesis in mammary explants. For this effect bivalency was essential, and down-regulation of receptors was much less than that produced by prolactin itself [50],... 

Calcitonin is a peptide hormone produced by the C cells of the thyroid gland (in mammals). It acts on bone (inhibiting osteoclasis) to reduce the rate of bone turnover, and on the kidney to reduce reabsorption of calcium and phosphorus. It is obtained from natural sources (pork, salmon, eel), or S3mthesised. The t/ varies according to source t/ human is 10 min. Antibodies develop particularly to pork calcitonin and neutralise its effect synthetic salmon calcitonin (salcatonin) is therefore preferred for prolonged use loss of effect may also be due to down-regulation of receptors. Calcitonin is used (s.c., i.m. or intranasally) to control hypercalcaemia (rapid effect), Paget s disease of bone (relief of pain, and to relieve compression of nerves, e.g. auditory cranial), metastatic bone cancer pain, and postmenopausal osteoporosis. 

Despite evidence for and against, there remains one major problem with the monoamine theory of depression. All antidepressants take weeks to have an effect, which is far longer than it takes to alter brain amines. It has been suggested that effects of antidepressants are due to adaptive changes in the brain, which may involve down regulation of receptors or some other change in their sensitivity. 

---