In the brain, the mu-opioid receptor (MOR) activates neural nitric oxide synthase (nNOS) through the PI3K/Akt pathway. The resulting nitric oxide (NO) enhances the function of the glutamate N-methyl-d-aspartate receptor (NMDAR)/calcium and calmodulin-dependent serine/threonine kinase (CaMKII), which subsequently diminishes MOR signaling strength. Because the ERK1/2 cascade is implicated in opioid tolerance, we analyzed the role of morphine-generated NO in this negative regulation. We found that NO-released endogenous zinc ions recruit the Ras/Raf-1/ERK1/2 cassette to histidine triad nucleotide-binding protein 1 (HINT1). A-Raf and B-Raf showed little or no MOR association. The zinc ions bridge the Raf-1 cysteine-rich domain (CRD) with HINT1 at the MOR C-terminus. Morphine also recruits PKCγ via NO/zinc to the MOR-HINT1 complex. Both Raf-1 and PKCγ CRDs bind simultaneously to HINT1, enabling PKCγ to enhance Raf-1 function to intensify MEK/ERK1/2 activation. Thus, through attached HINT1, the MOR facilitates the cross-talk of two NO- and zinc-regulated signal-transduction pathways, PKC/Src and Raf-1/ERK1/2, implicated in the negative control of morphine effects. This study reveals new aspects of ERK1/2 regulation by the MOR without requiring the transactivation of a receptor tyrosine kinase. Antioxid. Redox Signal. 14, 2413–2425
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