Brain-specific Galphaz interacts with Src tyrosine kinase to regulate Mu-opioid receptor-NMDAR signaling pathway.
There is a certain cross-talk in the nervous system between N-methyl-D-aspartate receptors (NMDARs) and Mu-opioid receptors (MORs). While NMDARs participate in the desensitization of MORs, these in turn modulate NMDAR-mediated glutamate responses. The G protein coupled receptors (GPCRs) activate NMDARs via Src although the role of Galpha subunits in this process is not well defined. We have found that in the absence of MOR activation, the brain specific Galphaz subunit binds to and stabilizes Src in its inactive form. The administration of morphine provokes the phosphorylation of specific cytosolic tyrosine residues in NMDAR2A subunits. This was achieved by PKCgamma disrupting this Galphaz-Src complex, enabling Src to be activated (pTyr416) by binding to GalphaiGTP proteins. These changes increased the activation of the calcium/calmodulin-dependent protein kinase II (CaMKII), thereby promoting MOR desensitization. This regulatory pathway is disrupted by inhibiting PKC, preventing MOR-activated Galphai2 subunits from gaining control over Src. Thus, in neural cells the Galphaz subunits exert a negative control on Src function reducing the activating influence of MORs on this tyrosine kinase. This MOR-triggered signaling pathway recruits PKCgamma and Galphai subunits to activate Src tyrosine kinase, resulting in the potentiation of NMDAR function. Most relevant, this mechanism which operates in neural cells is essential for the development of tolerance to the analgesic effects of morphine.
Sánchez-Blázquez
Pilar
P
Instituto Cajal CSIC, Madrid, Spain.
Rodríguez-Muñoz
María
M
de la Torre-Madrid
Elena
E
Garzón
Javier
J
D000818:Animals; D001921:Brain / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D044385:GTP-Binding Protein alpha Subunits; C490964:Gnaz protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D009020:Morphine; D016392:Proto-Oncogene Proteins pp60(c-src); D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018631:ras Proteins