A novel mechanism of neurokinin-1 receptor resensitization.
Animals; Cell Membrane/drug effects/metabolism; CHO Cells; Concanavalin A/pharmacology; Cricetinae; Monensin/pharmacology; Neurokinin-1/*agonists/*metabolism; Phosphorylation/drug effects; Rats; Receptors
Prolonged or repeated activation of many G protein-coupled receptors induces rapid desensitization followed by a period during which receptors are resensitized. In this study, concanavalin A (Con A) and monensin were used to investigate the mechanisms of desensitization and resensitization of the neurokinin-1 receptor. Con A inhibits internalization, whereas monensin prevents receptor recycling. The effects of Con A and monensin on desensitization, resensitization, receptor phosphorylation, endocytosis, and recycling of the neurokinin-1 receptor were assessed. Desensitization was defined as the decrease in the ability of substance P (SP) to elicit an intracellular Ca2+ response after a prolonged SP exposure. Resensitization was characterized as the return of SP responsiveness. Under control conditions, desensitization occurred after a 5-min exposure to agonist. Resensitization was evident 30 min after agonist washout. Neither monensin nor Con A prevented desensitization. Monensin completely inhibited resensitization, whereas Con A decreased but did not completely block resensitization. Receptor phosphorylation was increased after agonist activation and returned to basal levels after a recovery period. Neither Con A nor monensin altered the amount of agonist-specific receptor phosphorylation. Receptor binding analysis showed that plasma membrane receptors were internalized after a 5-min agonist exposure. Receptor recycling was not observed after a 1-h recovery period; however, resensitization was apparent. Taken together, these results suggest that rapid neurokinin-1 receptor desensitization can occur without receptor internalization and that resensitization occurs before receptor recycling.
Bennett V J; Perrine S A; Simmons M A
The Journal of pharmacology and experimental therapeutics
2002
2002-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/jpet.102.040378" target="_blank" rel="noreferrer noopener">10.1124/jpet.102.040378</a>
A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.
Calcitriol/*metabolism; Calcitriol/pharmacology; Cell Membrane/drug effects/metabolism; Cell Nucleus/drug effects/metabolism; Cholesterol 7-alpha-Hydroxylase/antagonists & inhibitors/genetics; Enzyme Activation/drug effects; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors; Genetic/genetics; Hep G2 Cells; Hepatocyte Nuclear Factor 4/metabolism; Hepatocytes/*drug effects/enzymology/*metabolism; Humans; Intracellular Space/drug effects/metabolism; Ligands; Lithocholic Acid/*pharmacology; Mitogen-Activated Protein Kinase Kinases/metabolism; Phosphorylation/drug effects; Phosphotyrosine/metabolism; Promoter Regions; Protein Kinase Inhibitors/pharmacology; Protein Transport/drug effects; Proto-Oncogene Proteins c-raf/metabolism; Receptors; Retinoid X Receptor alpha/metabolism; Signal Transduction/*drug effects; src-Family Kinases/metabolism; Steroid Hydroxylases/genetics/metabolism; Vitamin D3 24-Hydroxylase
Vitamin D receptor (VDR) is activated by natural ligands, 1alpha,
Han Shuxin; Li Tiangang; Ellis Ewa; Strom Stephen; Chiang John Y L
Molecular endocrinology (Baltimore, Md.)
2010
2010-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1210/me.2009-0482" target="_blank" rel="noreferrer noopener">10.1210/me.2009-0482</a>