Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization

Abstract

Agonist-activated μ-opioid receptor (OPRM1) undergoes robust receptor phosphorylation by G protein-coupled receptor kinases and subsequent β-arrestin recruitment, triggering receptor internalization and desensitization. Morphine, a widely prescribed opioid, induces receptor phosphorylation inefficiently. Previously we reported that FK506 binding protein 12 (FKBP12) specifically interacts with OPRM1 and such interaction attenuates receptor phosphorylation and facilitates morphine-induced recruitment and activation of protein kinase C. In the current study, we demonstrated that the association of FKBP12 with OPRM1 also affects morphine-induced receptor internalization and G protein-dependent adenylyl cyclase desensitization. Morphine induced faster receptor internalization and adenylyl cyclase desensitization in cells expressing OPRM1 with Pro353mutated to Ala (OPRM1P353A), which does not interact with FKBP12, or in the presence of FK506 which dissociates the receptor-FKBP12 interaction. Furthermore, knockdown of cellular FKBP12 level by siRNA accelerated morphine-induced receptor internalization and adenylyl cyclase desensitization. Our study further demonstrated that peptidyl prolyl cis-trans isomerase activity of FKBP12 probably plays a role in inhibition of receptor phosphorylation. In the view that internalized receptor recycles and thus counteracts the development of analgesic tolerance, receptor’s association with FKBP12 could also contribute to the development of morphine tolerance through modulation of receptor trafficking.

Opioid receptor desensitization: mechanisms and its link to tolerance

“…As they also demonstrated that PKC mediated morphine-induced MOR desensitization, it can be inferred that PKC would phosphorylate MOR at other sites than S363, T370, and S375. MOR desensitization and phosphorylation at S375 produced by morphine can be modulated by other proteins such as the FK binding protein 12 which would compete with kinase at MOR (Yan et al, 2014 ).…”

Yeast one-hybrid screening the potential regulator of CYP6B6 overexpression ofHelicoverpa armigeraunder 2-tridecanone stress

“…FKBPs are natural homologous receptors of immunosuppressant FK506 protein in the prokaryotic and eukaryotic cells. They can catalyze the bond conformation of N-terminal proline residues from the cis to the trans, thus affecting the protein activity, phosphorylation, protein–protein interaction, subcellular localization and stability of protein substrate (Yan et al , 2014). The binding of FK506 and FKBP12 could inhibit the mammalian target of rapamycin (mTOR) signal transduction to affect gene transcription.…”

Annexin A2 traps mu-opioid receptors in recycling endosomes upon remifentanil-induced internalization

“…Knockdown of dynamin abolished DAMGO-induced MOR1 internalization and caused DAMGO tolerance ( Ueda et al, 2001 ). In contrast, opioid-induced acute analgesic tolerance could be prevented by PKC inhibition ( Ueda et al, 2001 ) or knockdown of cellular FK506 binding protein 12 (FKBP12) ( Yan et al, 2014 ), which leads to MOR1 internalization. One plausible theory underlying these processes is that MOR1 internalization followed by rapid recycling contributes to its functional re-sensitization and counteracts opioid tolerance ( Koch and Höllt, 2008 ).…”