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- W2054278293 abstract "One mechanism of long-term agonist-promoted desensitization of α2AR function is downregulation of the cellular levels of the α subunit of the inhibitory G protein, Gi. In transfected CHO cells expressing the human α2AAR, a 40.1 ± 3.3% downregulation of Gαi2 protein occurred after 24 h of exposure of the cells to epinephrine, which was not accompanied by a decrease in Gαi2 mRNA. The essential step that targets Gi for degradation by agonist occupancy of the receptor was explored using mutated α2AAR lacking specific structural or functional elements. These consisted of 5HT1A receptor and β2AR sequences substituted at residues 113−149 of the second intracellular loop and 218−235 and 355−371 of the N- and C-terminal regions of the third intracellular loop (altered Gi and Gs coupling), deletion of Ser296−299 (absent GRK phosphorylation), and substitution of Cys442 (absent palmitoylation and receptor downregulation). Of these mutants, only those with diminished Gi coupling displayed a loss of agonist-promoted Gi downregulation, thus excluding Gs coupling and receptor downregulation, palmitoylation, and phosphorylation as necessary events. Furthermore, coupling-impaired receptors consisting of mutations in the second or third loops ablated Gi downregulation, suggesting that a discreet structural motif of the receptor is unlikely to represent a key element in the process. While pertussis toxin ablated Gi downregulation, blocking downstream intracellular consequences of α2AAR activation or mimicking these pathways by heterologous means failed to implicate cAMP/adenylyl cyclase, phospholipase C, phospholipase D, or MAP kinase pathways in α2AAR-mediated Gi downregulation. Taken together, agonist-promoted Gi downregulation requires physical α2AAR−Gi interaction which targets Gi for degradation in a manner that is independent of α2AAR trafficking, regulation, or second messengers." @default.
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- W2054278293 date "1998-10-14" @default.
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- W2054278293 title "Agonist-Mediated Downregulation of G<sub>α</sub><sub>i</sub> via the α<sub>2</sub>-Adrenergic Receptor Is Targeted by Receptor-G<sub>i</sub> Interaction and Is Independent of Receptor Signaling and Regulation" @default.
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- W2054278293 doi "https://doi.org/10.1021/bi980999r" @default.
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