Plasma membrane localization of the mu-opioid receptor controls spatiotemporal signaling
Michelle L Halls, Holly R Yeatman, Cameron J Nowell, Georgina L Thompson, Arisbel Batista Gondin, Srgjan Civciristov, Nigel W Bunnett, Nevin A Lambert, Daniel P Poole, Meritxell Canals
SCIENCE SIGNALING | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2016
Differential regulation of the μ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. We used biophysical approaches to quantify spatiotemporal MOR signaling in response to different ligands. In human embryonic kidney (HEK) 293 cells overexpressing MOR, morphine caused a Gβγ-dependent increase in plasma membrane-localized protein kinase C (PKC) activity, which resulted in a restricted distribution of MOR within the plasma membrane and induced sustained cytosolic extracellular signal-regulated kinase (ERK) signaling. In contrast, the synthetic opioid pepti..View full abstract
Awarded by National Health and Medical Research Council (NHMRC) RD Wright Fellowship
Awarded by NHMRC Australia Fellowship
Awarded by NHMRC Project Grants
We thank D. D. Jensen for technical assistance; M. J. Christie for critical discussion; R. J. Summers, J. R. Lane, and A. M. Ellisdon for careful review of this manuscript; and L. Bohn, S. Schulz, and M. Caron for providing DNAs. Funding: This work was supported by a Monash Fellowship to M.C.; National Health and Medical Research Council (NHMRC) RD Wright Fellowship to M.L.H. (1061687); NHMRC Australia Fellowship to N.W.B. (63303); NHMRC Project Grants (1011796, 1047633, 1049682, and 1031886) to M.C., M.L.H., and N.W.B.; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences Large Grant Support Scheme grants to M.C. and M.L.H.; and Monash University support to N.W.B. G.L.T. is funded by DSTO (Defence Science and Technology Organisation) Australia.