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Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked μ, δ, and κ opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective μ or δ opioid receptor agonists are lost in AC5-/- mice, whereas the behavioral effects of selective κ opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a μ or δ opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5-/- mice. Together, these results establish AC5 as an important component of μ and δ opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action. [ABSTRACT FROM AUTHOR]

The transmembrane protein Notch is cleaved by γ-secretase to yield an active form, Notch intracellular domain (Notch-IC), in response to the binding of ligands. such as Jagged. Notch-IC contributes to the regulation of a variety of cellular events, including cell fate determination during embryonic development as well as cell growth, differentiation, and survival. We now show that Notch1-IC suppresses the scaffold activity of c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1) in the JNK signaling path-way. Notch1-IC physically associated with the JNK binding domain of JIP1 and thereby interfered with the interaction between JIPI and JNK. JIP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts, and ectopic expression of Notch1-IC inhibited INK activation and apoptosis triggered by glucose deprivation. Taken together, these findings suggest that Notch1-IC negatively regulates the JNK pathway by disrupting the scaffold function of JIP1. [ABSTRACT FROM AUTHOR]