Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor desensitization provides a potential mechanism for the regulation of adrenocortical adrenocorticotropin (ACTH) responsiveness. Using the mouse adrenocortical Y1 cell line we demonstrate that ACTH effectively desensitizes the cAMP response of its own receptor, the melanocortin 2 receptor (MC2R), in these cells with a maximal effect between 30 and 60 min. Neither forskolin nor isoproterenol (in Y1 cells stably transfected with the beta(2)-adrenergic receptor) desensitize this ACTH response. ACTH desensitizes its receptor at concentrations at which only a fraction of receptors are occupied, implying that this mechanism acts on agonist-unoccupied receptors. Y1 cells express G protein-coupled receptor kinase (GRK) 2 and 5, but stable expression of a dominant negative GRK2 (K220W) only marginally reduces the desensitization by ACTH. The protein kinase A (PKA) inhibitor, H89, extinguishes almost the entire desensitization response over the initial 30-min period at all concentrations of ACTH. A mutant MC2R in which the single consensus PKA phosphorylation site has been mutated (S208A) when expressed in MC2R-negative Y6 cells is also unable to desensitize. These data imply a heterologous, PKA-dependent, mode of desensitization, which is restricted to agonist-occupied and -unoccupied MC2R, possibly as a consequence of receptor/effector complexes that functionally compartmentalize this receptor.
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PMID:Desensitization of the Y1 cell adrenocorticotropin receptor: evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes. 1157 4

Disruption of the hypothalamic melanocortin-4 receptor (MC4R) pathway results in obesity both in humans and rodents, demonstrating a crucial role for hypothalamic MC4Rs in the regulation of energy homeostasis. Because even haploinsufficiency of the MC4R gene can cause obesity in humans and mice, subtle changes in receptor numbers or signaling are likely to impact upon the regulation of food intake and energy expenditure. Little is known about the intracellular regulation of MC4R signaling. Using GT1-7 cells, we show for the first time that the MC4R undergoes ligand-mediated desensitization. We then addressed the possible mechanisms underlying the desensitization using HEK293 and COS-1 cells transfected with hemagglutinin-tagged human MC4R. Preexposure of GT1-7 cells that express endogenous MC4R to the agonist for MC4R, alpha-melanocyte-stimulating hormone, resulted in impaired cAMP formation to a second challenge of alpha-melanocyte-stimulating hormone. The desensitization of MC4R was accompanied by time-dependent internalization of the receptor in HEK293 cells, which was partly inhibited by pretreatment with a specific protein kinase A (PKA) inhibitor, H89. In COS-1 cells, overexpression of dominant-negative G protein-coupled receptor kinase (GRK) 2-K220R partly inhibited the agonist-mediated internalization of MC4R, whereas it did not in HEK293 cells. Overexpression of dominant-negative mutants of beta-arrestin1-V53D and dynamin I-K44A prevented agonist-mediated internalization of MC4R. Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. Our data demonstrate that, through PKA-, GRK-, beta-arrestin-, and dynamin-dependent processes, MC4R undergoes internalization in response to agonist, thereby providing novel insights into the regulation of MC4R signaling.
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PMID:Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. 1263 13

Corticotropin-releasing factor (CRF), produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, stimulates the synthesis and secretion of adrenocorticotropin (ACTH) via CRF receptor type 1 (CRF(1) receptor) in the anterior pituitary (AP) of mammals. CRF is critical for the circadian rhythmicity of the hypothalamic-pituitary-adrenal axis and the augmented release of ACTH from the pituitary in response to the stress. A higher molecular weight form of immunoreactive beta-endorphin, putative proopiomelanocortin (POMC), is increased in CRF-knockout mice (CRF KO), suggesting the important role of CRF in the processing of POMC. In fact, CRF is able to modulate the processing of POMC through changes in prohormone convertase (PC)-1 expression levels. Multiple forms of ACTH-related peptides containing unprocessed ones are present in some cases of ACTH-producing tumors, presumably without action of PC-1 under the control of CRF. Following CRF-activated stimulation of the receptor signaling, CRF(1) receptor is down-regulated and desensitized. In fact, CRF facilitates the degradation of CRF(1) receptor mRNA via the protein kinase A pathway. Prolonged agonist activation of CRF(1) receptor leads to a loss of responsiveness, or desensitization of the receptor. G protein-coupled receptor kinase 2 is involved in desensitization of CRF(1) receptor by CRF in the corticotroph.
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PMID:Role and action in the pituitary corticotroph of corticotropin-releasing factor (CRF) in the hypothalamus. 1912 55