Abstract
The endogenous cannabinoid system plays an important role in the regulation of gastrointestinal function in health and disease. Endocannabinoid levels are regulated by catabolic enzymes. Here, we describe the presence and localization of monoacylglycerol lipase (MGL), the major enzyme responsible for the degradation of 2-arachidonoylglycerol. We used molecular, biochemical, immunohistochemical, and functional assays to characterize the distribution and activity of MGL. MGL mRNA was present in rat ileum throughout the wall of the gut. MGL protein was distributed in the muscle and mucosal layers of the ileum and in the duodenum, proximal colon, and distal colon. We observed MGL expression in nerve cell bodies and nerve fibers of the enteric nervous system. There was extensive colocalization of MGL with PGP 9.5 and calretinin-immunoreactive neurons, but not with nitric oxide synthase. MGL was also present in the epithelium and was highly expressed in the small intestine. Enzyme activity levels were highest in the duodenum and decreased along the gut with lowest levels in the distal colon. We observed both soluble and membrane-associated enzyme activities. The MGL inhibitor URB602 significantly inhibited whole gut transit in mice, an action that was abolished in cannabinoid 1 receptor-deficient mice. In conclusion, MGL is localized in the enteric nervous system where endocannabinoids regulate intestinal motility. MGL is highly expressed in the epithelium, where this enzyme may have digestive or other functions yet to be determined.
Highlights
CANNABINOID (CB) receptors, the endogenous ligands for these receptors, and their biosynthetic and catabolic enzymes form the endocannabinoid system [11, 12]
monoacylglycerol lipase (MGL) is expressed along the length of the GI tract in the full-wallthickness samples of duodenum, ileum, proximal colon, and distal colon (Fig. 1B)
We report that the endocannabinoid hydrolyzing enzyme MGL is widely distributed in the rodent GI tract
Summary
CANNABINOID (CB) receptors (termed CB1 and CB2), the endogenous ligands for these receptors (endocannabinoids), and their biosynthetic and catabolic enzymes form the endocannabinoid system [11, 12]. Endocannabinoids are synthesized and released “on demand.” Their biosynthetic and inactivation pathways have been identified. Anandamide is present in ileal and colonic tissues at levels of 0.27 and 0.036 nmol/g, whereas 2-AG levels are 44.1 and 18.7 nmol/g, respectively [38] Such regional differences of endocannabinoids along the GI tract may reflect functional differences in their actions in the ileum and colon. FAAH mRNA and protein expression is present in the GI tract [4] and inhibition significantly attenuates intestinal motility in mice, indicating that enhanced local endocannabinoid levels are functionally significant [23].
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More From: American Journal of Physiology-Gastrointestinal and Liver Physiology
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