Separation of Acute Desensitization and Long-Term Tolerance of µ-Opioid Receptors Is Determined by the Degree of C-Terminal Phosphorylation.

Molecular Pharmacology
Seksiri ArttamangkulJohn T Williams

Abstract

Phosphorylation of sites on the C terminus of the μ-opioid receptor (MOR) results in the induction of acute desensitization that is thought to be a precursor for the development of long-term tolerance. Alanine mutations of all 11 phosphorylation sites on the C terminus of MORs almost completely abolished desensitization and one measure of tolerance in locus coeruleus neurons when these phosphorylation-deficient MORs were virally expressed in MOR knockout rats. In the present work, we identified specific residues that underlie acute desensitization, receptor internalization, and tolerance and examined four MOR variants with different alanine or glutamate mutations in the C terminus. Alanine mutations in the sequence between amino acids 375 and 379 (STANT-3A) and the sequence between amino acids 363 and 394 having four additional alanine substitutions (STANT + 7A) reduced desensitization and two measures of long-term tolerance. After chronic morphine treatment, alanine mutations in the sequence between 354 and 357 (TSST-4A) blocked one measure of long-term tolerance (increased acute desensitization and slowed recovery from desensitization) but did not change a second (decreased sensitivity to morphine). With the expression of rec...Continue Reading

References

Jun 13, 2003·Biomedical Engineering Online·Thomas A PologrutoKarel Svoboda
Sep 3, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Vu C Dang, John T Williams
Mar 13, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Vu C DangMacDonald J Christie
Mar 25, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nidia QuillinanJohn T Williams
Apr 1, 2011·British Journal of Pharmacology·Christian DollStefan Schulz
Aug 24, 2012·Molecular Pharmacology·Erica S Levitt, John T Williams
Oct 31, 2012·Journal of Neurochemistry·Ying-Ju ChenEamonn Kelly
Dec 15, 2012·Molecular Pharmacology·Sascha JustStefan Schulz
Jan 17, 2013·Pharmacological Reviews·John T WilliamsMacdonald J Christie
Mar 1, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·William T BirdsongJohn T Williams
Apr 22, 2014·Molecular Pharmacology·John T Williams
May 15, 2015·Molecular Pharmacology·Arsalan YousufMacDonald J Christie
Feb 14, 2018·Science Signaling·Ganesh V PusapatiRajat Rohatgi
Mar 29, 2018·ELife·Seksiri ArttamangkulJohn T Williams

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Citations

Mar 22, 2020·Molecular Pharmacology·William T Birdsong, John T Williams
Mar 22, 2020·Molecular Pharmacology·Damien JulliéMeritxell Canals
May 5, 2020·Molecular Pharmacology·Emily R LeffJohn T Williams
Apr 3, 2020·Molecular Pharmacology·Renee A BouleyJohn J G Tesmer
Nov 6, 2020·Cells·Laura LemelMeritxell Canals
May 28, 2020·Trends in Neurosciences·Mariana Lemos Duarte, Lakshmi A Devi
Nov 1, 2020·Trends in Biochemical Sciences·Javier CuitaviMeritxell Canals
Apr 9, 2021·Peptides·Richard J Bodnar
Apr 29, 2021·Cell Reports·Nohely AbreuJoshua Levitz
May 10, 2021·Current Opinion in Cell Biology·Jennifer M KunselmanManojkumar A Puthenveedu

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