Mitogen-activated protein kinases inhibition

Lazar, D.F., Wiese, R.J., Brady, M.J., Mastick, C.C., Waters, S.B., Yamauchi, K., Pessin, J.E., Cuatrecasas, P. and Saltiel, A.R. Mitogen-activated protein kinase inhibition does not block the stimulation of glucose utilization by insulin. J. Biol. Chem., 1995, 270, 20801-20807. 

Bouaboula, M., Perrachon, S., Milligan, L., Canatt, X., Rinaldi-Carmona, M., Portier, M., Barth, F., Calandra, B., Pecceu, F., Lupker, J., Maffrand, J.-P., Le Fur, G., and Casellas, P. (1997). A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor. J. Biol. Ckem. 272 22330-22339. 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Activation of Mi, M3, and M5 mAChRs does not only lead to the generation of IP3 followed by the mobilization of intracellular Ca2+, but also results in the stimulation of phospholipase A2, phospholipase D, and various tyrosine kinases. Similarly, M2 and M4 receptor activation does not only mediate the inhibition of adenylyl cyclase, but also induces other biochemical responses including augmentation of phospholipase A2 activity. Moreover, the stimulation of different mAChR subtypes is also linked to the activation of different classes of mitogen-activated protein kinases (MAP kinases), resulting in specific effects on gene expression and cell growth or differentiation. 

The OP group of receptois share common effector mechanisms. All receptois couple via pertussis toxin-sensitive Go and Gi proteins leading to (i) inhibition of adenylate cyclase (ii) reduction of Ca2+ currents via diverse Ca2+ channels (hi) activation of inward rectifying K+ channels. In addition, the majority of these receptors cause the activation of phospholipase A2 (PLA2), phospholipase C 3 (PLC 3), phospholipase D2 and of MAP (mitogen-activated protein) kinase (Table 3). 

The biochemical mechanism of Mos action is not yet established. Mos has been found to phosphorylate cyclin B in vitro, and it is possible that this phosphorylation directly inhibits cyclin B proteolysis (Roy et al., 1990). However, such a direct effect of phosphorylation on cyclin B stability remains to be demonstrated, and it is alternatively possible that Mos inhibits (directly or indirectly) the proteolytic pathway responsible for cyclin B degradation. Mos has recently been found to stimulate mitogen-activated protein kinase (MAP kinase) in Xenopus oocytes,... 

Kim, G-Y, KimJ-H, AhnS-C et al. 2004. Lycopene suppresses the lipopolysaccharide-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and nuclear factor NF-kappa B. Immunology 113 203-211. 

Kim, Y., Chongviriyaphan, N., Liu, C., Russell, R.M., and Wang, X.D. 2006. Combined antioxidant (beta-carotene, alpha-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model. 

Zeyda, M. et al., Suppression of T cell signaling by polyunsaturated fatty acids Selectivity in inhibition of mitogen-activated protein kinase and nuclear factor activation, J Immunol, 170, 6033, 2003. 

Two processes have been proposed to explain the mitogenic effect of fluoride on bone cells involving either fluoride ions directly or the AIF complex (Fig. 11). Fluoride ions have been shown to directly inhibit an enzyme (tyrosine phophory-lase phosphatase) resulting in an enhancement of the tyrosine phosphorylation part of the mitogen-activated protein kinase system (MARK) [177], The other activation pathway involves a complex of aluminium and fluoride which activates the G-protein and stimulates tyrosine phophorylation resulting in an enhanced mitogenic effect [176]. 

The nature of the second messenger response to a given neurotransmitter depends on the subtype of receptor to which it binds and the G protein to which the receptor is coupled. Three of the most commonly utilized G proteins include G, which stimulates adenylyl cyclase to produce cyclic AMP (cAMP) Gj, which inhibits adenylyl cyclase, resulting in lower intracellullar levels of cAMP and Gq, which activates phospholipase C to produce the second messengers IP3 and DAG. In general, these activities refer to the function of the a subunit however, it should be pointed out that the py complex has its own set of activities (on adenylyl cyclase, phospholipase C, channels, mitogen-activated protein kinase [MAPK]) that are just now becoming better clarified. 

---