Divergent and convergent signaling by the diacylglycerol second messenger pathway in mammals

Brose, Nils; Betz, Andrea; Wegmeyer, Heike

doi:10.1016/j.conb.2004.05.006

Cited by 117 publications

(90 citation statements)

References 109 publications

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“…It is generated by the hydrolysis of phosphatidylinositol 4,5-bisphosphate in response to the activation of surface receptors that include GPCRs and receptor tyrosine kinases [26]. In addition to its many cellular functions, DAG can also serve as a substrate for enzymes that generate alternative signalling lipids [27].…”

Section: The Many Facets Of Endocannabinoidsmentioning

confidence: 99%

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Skaper

Marzo²

2012

Phil. Trans. R. Soc. B

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The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.

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Section: The Many Facets Of Endocannabinoidsmentioning

confidence: 99%

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Skaper

Marzo²

2012

Phil. Trans. R. Soc. B

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“…DAG is an allosteric activator of protein kinase C (PKC) (3) as well as nonkinase proteins such as GTPase-activating proteins and guanine nucleotide exchange factors for the Ras family of GTPases (4,5). Termination of the DAG-derived signal must be rapid and requires DGK activity.…”

Section: Diacylglycerol Kinase (Dgk)mentioning

confidence: 99%

Modulation of the Mammalian Target of Rapamycin Pathway by Diacylglycerol Kinase-produced Phosphatidic Acid

Ávila-Flores

Santos

Rincón

et al. 2005

Journal of Biological Chemistry

135

111

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The protein known as mammalian target of rapamycin (mTOR) regulates cell growth by integrating different stimuli, such as available nutrients and mitogenic factors. The lipid messenger phosphatidic acid (PA) binds and positively regulates the mitogenic response of mTOR. PA generator enzymes are consequently potential regulators of mTOR. Here we explored the contribution to this pathway of the enzyme diacylglycerol kinase (DGK), which produces PA through phosphorylation of diacylglycerol. We found that overexpression of the DGK, but not of the ␣ isoform, in serum-deprived HEK293 cells induced mTOR-dependent phosphorylation of p70S6 kinase (p70S6K). After serum addition, p70S6K phosphorylation was higher and more resistant to rapamycin treatment in cells overexpressing DGK. The effect of this DGK isoform on p70S6K hyperphosphorylation required the mTOR PA binding region. Down-regulation of endogenous DGK by small interfering RNA in HEK293 cells diminished serum-induced p70S6K phosphorylation, highlighting the role of this isoform in the mTOR pathway. Our results confirm a role for PA in mTOR regulation and describe a novel pathway in which DGK-derived PA acts as a mediator of mTOR signaling.

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“…Studies in cell lines demonstrated that ␣-chimaerins have GAP activity toward Rac1 and to a lesser extent toward Cdc42 (16,17). Moreover, ␣-chimaerins are members of an emerging family of non-PKC phorbol ester receptors that bind diacylglycerol (DAG) through a C1 domain (18). Chimaerins may therefore link lipid signaling and Rac inactivation.…”

mentioning

confidence: 99%

The diacylglycerol-binding protein α1-chimaerin regulates dendritic morphology

Buttery

Beg

Chih

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The morphological and functional differentiation of neuronal dendrites is controlled through transcriptional programs and cell-cell signaling. Synaptic activity is thought to play an important role in the maturation of dendritic arbors, but the signaling pathways that couple neuronal activity and morphological changes in dendrites are not well understood. We explored the function of ␣1-chimaerin, a neuronal diacylglycerol-binding protein with a Rho GTPaseactivating protein domain that inactivates Rac1. We find that stimulation of phospholipase C␤-coupled cell surface receptors recruits ␣1-chimaerin to the plasma membrane of cultured hippocampal neurons. We further show that ␣1-chimaerin protein levels are controlled by synaptic activity and that increased ␣1-chimaerin expression results in the pruning of dendritic spines and branches. This pruning activity requires both the diacylglycerolbinding and Rac GTPase-activating protein activity of ␣1-chimaerin. Suppression of ␣1-chimaerin expression resulted in increased process growth from the dendritic shaft and from spine heads. Our data suggest that ␣1-chimaerin is an activity-regulated Rho GTPase regulator that is activated by phospholipase C␤-coupled cell surface receptors and contributes to pruning of dendritic arbors.spine ͉ neuronal activity ͉ phospholipase C ͉ pruning

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Divergent and convergent signaling by the diacylglycerol second messenger pathway in mammals

Cited by 117 publications

References 109 publications

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Modulation of the Mammalian Target of Rapamycin Pathway by Diacylglycerol Kinase-produced Phosphatidic Acid

The diacylglycerol-binding protein α1-chimaerin regulates dendritic morphology

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