Modulation by calcium/calmodulin-dependent protein kinase II of functional response of delta opioid receptor in neuroblastoma x glioma hybrid (NG108-15) cells.
The potential modulation of opioid receptor signaling by calcium/calmodulin-dependent protein kinase II (CaMKII) has been investigated in NG108-15 cells. Both CaMKII specific inhibitors used, KN62 and KN93, time- and dose-dependently blocked inhibition of cAMP accumulation by [D-Pen2, D-Pen5]enkephalin (DPDPE), with an IC50 of about 1.2 microM and 0.8 microM, respectively. In the presence of 1 microM KN62 or KN93, the DPDPE dose-response curve shifted to the right (IC50 from 0.7 to 20 nM for KN62 and from 0.65 to 10 nM for KN93, respectively), and the maximal response was also significantly reduced. KN92, an inactive analogue of KN93, showed no significant impact, while ionomycin, an activator of CaMKII, greatly potentiated the opioid receptor response, suggesting that the effects of KN62, KN93 and ionomycin were likely mediated through CaMKII. In addition, KN62 did not affect ligand binding, receptor/Gi coupling, or basal and forskolin-stimulated adenylyl cyclase activity, suggesting its possible interference in the Gi/adenylyl cyclase interaction. Furthermore, a CaMKII inhibitor potently blocked the functional responses of other Gi-coupled receptors (m4 muscarinic and alpha2 adrenergic receptors) tested, but not that of Gs-coupled receptors (prostaglandin E1 and adenosine receptors). Our results clearly demonstrate that CaMKII modulates the signaling of opioid receptor and other Gi-coupled receptors.
Fan
G H
GH
Shanghai Institute of Cell Biology, Chinese Academy of Sciences, People's Republic of China.
Zhang
W B
WB
Yao
C P
CP
Pei
G
G
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005910:Glioma / Q000201:enzymology / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000067956:Adenylyl Cyclase Inhibitors; D000700:Analgesics; D004745:Enkephalins; D004791:Enzyme Inhibitors; D007476:Ionophores; D017465:Receptors, Opioid, delta; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases