Selective interference of beta-arrestin 1 with kappa and delta but not mu opioid receptor/G protein coupling.
The role of beta-arrestin 1 (beta-arr1) in regulation of responsiveness of kappa, delta, and mu opioid receptors has been investigated in human embryonic kidney 293 cells cotransfected with opioid receptor and beta-arr1. Expression of human beta-arr1 attenuated kappa and delta opioid receptor subtype-mediated inhibition of cAMP production and resulted in a 100-fold increase of EC50 values for kappa-agonist U69593 and delta-agonist [D-Pen2, D-Pen5]enkephalin and 30-40% reduction of their maximal responses. In contrast, coexpression of beta-arr1 with mu opioid receptor did not affect the concentration-effect relationship of mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. In parallel, kappa and delta receptor-mediated G protein activation was also remarkably attenuated by overexpression of beta-arr1, while the mu-agonist-stimulated response remained intact. These results indicate that beta-arr1 interferes receptor/G protein coupling and differentially regulates the responsiveness of opioid receptors. Truncation of kappa and delta opioid receptors at carboxyl termini abolished inhibition of beta-arr1 on the responsiveness of both receptors. Furthermore, mu opioid receptor became sensitive to beta-arr1 regulation following replacement of its carboxyl terminus with the corresponding portion of the delta receptor. Removal of potential phosphorylation sites on the carboxyl terminus of kappa opioid receptor led to reduced effect of beta-arr1 on the receptor-mediated response. These results suggest that receptor carboxyl terminus and its phosphorylation play an important role in the interaction of beta-arr1 and opioid receptors.
Cheng
Z J
ZJ
Shanghai Institute of Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
Yu
Q M
QM
Wu
Y L
YL
Ma
L
L
Pei
G
G
D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D044482:Benzeneacetamides; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000737:chemistry / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000737:chemistry / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D000067956:Adenylyl Cyclase Inhibitors; D000700:Analgesics; D019390:Arrestins; D044482:Benzeneacetamides; D004745:Enkephalins; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; C045444:U 69593