Phosphoinositide 3-kinase cascade facilitates mu-opioid desensitization in sensory neurons by altering G-protein-effector interactions

作者：Tan M; Groszer M; Tan AM; Pandya A; Liu X; Xie CW^*

来源：Journal of Neuroscience, 2003, 23(32): 10292-10301.

DOI：10.1523/jneurosci.23-32-10292.2003

• PI 3-kinase
• Ca2+ channel
• opioid
• desensitization
• Akt
• PTEN

Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. Here we investigated the role of phosphoinositide 3-kinase (PI3K) and its downstream pathways in desensitization of mu-opioid inhibition of neuronal Ca2+ channels. In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the mu agonist [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO). Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). A combined application of PI3K and MAPK inhibitors showed no additive effect, suggesting that these two kinases act in a common pathway to facilitate chronic desensitization. Acute DAMGO desensitization, however, was not affected by the inhibitors. Furthermore, upregulation of the PI3K-Akt pathway in mutant mice lacking phosphatase and tensin homolog, a lipid phosphatase counteracting PI3K, selectively enhanced chronic desensitization in a PI3K- and MAPK-dependent manner. Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between betagamma subunits of G-proteins and Ca2+ channels. DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. Such disruption could occur at the postreceptor level, because chronic DAMGO also reduced GTPgammaS-induced PPF that was independent of receptor activation. Again, inhibition of PI3K or MAPK reduced desensitization of PPF. Our data suggest that the PI3K cascade involving MAPK and Akt enhances mu-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions.

• 出版日期2003-11-12