Evguenia V Kouranova

Publications (2)11.65 Total impact

• Article: Monoacylglycerol lipase activity is a critical modulator of the tone and integrity of the endocannabinoid system.

  Pranab K Chanda, Ying Gao, Lilly Mark, Joan Btesh, Brian W Strassle, Peimin Lu, Michael J Piesla, Mei-Yi Zhang, Brendan Bingham, Albert Uveges, Dianne Kowal, David Garbe, Evguenia V Kouranova, Robert H Ring, Brian Bates, Menelas N Pangalos, Jeffrey D Kennedy, Garth T Whiteside, Tarek A Samad
  [show abstract] [hide abstract]
  ABSTRACT: Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.
  Molecular pharmacology 12/2010; 78(6):996-1003. · 4.53 Impact Factor
• Article: Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.

  Ying Gao, Dmitry V Vasilyev, Maria Beatriz Goncalves, Fiona V Howell, Carl Hobbs, Melina Reisenberg, Ru Shen, Mei-Yi Zhang, Brian W Strassle, Peimin Lu, [......], Kangwen Deng, Evguenia V Kouranova, Robert H Ring, Garth T Whiteside, Brian Bates, Frank S Walsh, Gareth Williams, Menelas N Pangalos, Tarek A Samad, Patrick Doherty
  [show abstract] [hide abstract]
  ABSTRACT: Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.
  Journal of Neuroscience 02/2010; 30(6):2017-24. · 7.11 Impact Factor