|Sci Rep. 2016 Sep 19;6:33302. doi: 10.1038/srep33302.|
Human CB1 Receptor Isoforms, present in Hepatocytes and ß-cells, are Involved in Regulating Metabolism.
González-Mariscal I1, Krzysik-Walker SM1, Doyle ME2, Liu QR1, Cimbro R2, Santa-Cruz Calvo S1, Ghosh S1, Ciesla L1, Moaddel R1, Carlson OD1, Witek RP3, O'Connell JF1, Egan JM1.
1Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
3Thermo Fisher Scientific, 7300 Governor's Way, Frederick, MD 21704 USA.
Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic ß-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in ß-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in ß-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism.
Biochem Pharmacol. 2016 Sep 15. pii: S0006-2952(16)30287-8. doi: 10.1016/j.bcp.2016.09.008. [Epub ahead of print]
?9-Tetrahydrocannabinol Reverses TNFa-induced Increase in Airway Epithelial Cell Permeability through CB2 Receptors.
Shang VC1, Kendall DA1, Roberts RE2.
1Cell Signalling and Pharmacology Research Group, School of Life Sciences, University of Nottingham, Medical School, Nottingham, UK, NG7 2UH.
2Cell Signalling and Pharmacology Research Group, School of Life Sciences, University of Nottingham, Medical School, Nottingham, UK, NG7 2UH. Electronic address: firstname.lastname@example.org.
Despite pharmacological treatment, bronchial hyperresponsiveness continues to deteriorate as airway remodelling persists in airway inflammation. Previous studies have demonstrated that the phytocannabinoid ?9-tetrahydrocannabinol (THC) reverses bronchoconstriction with an anti-inflammatory action. The aim of this study was to investigate the effects of THC on bronchial epithelial cell permeability after exposure to the pro-inflammatory cytokine, TNFa. Calu-3 bronchial epithelial cells were cultured at air-liquid interface. Changes in epithelial permeability were measured using transepithelial electrical resistance (TEER), then confirmed with a paracellular permeability assay and expression of tight junction proteins by Western blotting. Treatment with THC prevented the TNFa-induced decrease in TEER and increase in paracellular permeability. Cannabinoid CB1 and CB2 receptor-like immunoreactivity was found in Calu-3 cells. Subsequent experiments revealed that pharmacological blockade of CB2, but not CB1 receptor inhibited the THC effect. Selective stimulation of CB2 receptors displayed a similar effect to that of THC. TNFa decreased expression of the tight junction proteins occludin and ZO-1, which was prevented by pre-incubation with THC. These data indicate that THC prevents cytokine-induced increase in airway epithelial permeability through CB2 receptor activation. This highlights that THC, or other cannabinoid receptor ligands, could be beneficial in the prevention of inflammation-induced changes in airway epithelial cell permeability, an important feature of airways diseases.