My research focuses on endocannabinoid anandamide (arachidonyl ethanolamide; a bioactive lipid) and its G-protein coupled receptors (GPCRs)-mediated molecular cell signaling in relation to angiogenesis and neurogenesis under normal physiological as well as pathological conditions. Endogenous cannabinoid anandamide produces its physiological responses acting on CB1 and CB2 cannabinoid receptors. Recent studies from my laboratory and others have indicated the existence of a novel non- CB1/CB2 "anandamide receptor" in different endothelial and tumor cells. We have shown that the activation of this putative "anandamide receptor" leads to Gi protein activation, nitric oxide (NO) production, cell migration and angiogenesis while activation of CB1 receptor inhibits angiogenesis. We are currently engaged in the cloning of the novel Gi-protein coupled"non-CB1/CB2 anandamide receptor and characterization of its signaling complex using a proprietary single-chain phage antibody library. Further, we have undertaken several projects in the laboratory to identify and characterize the molecular signaling mechanism of "anandamide receptor", CB1 and CB2 cannabinoid receptor -mediated regulation of angiogenesis in relation to the matrix metalloprotease activity. In a related project using an orthotopic animal model of prostate cancer we are investigating the role of CB1 and CB2 cannabinoid receptor in the regulation of androgen-sensitive prostate cancer cells growth, metastasis and tumor angiogenesis. In parallel to working on mammalian system, recently we have initiated projects to study the role of CB1 receptor in the regulation of angiogenesis and vasculogenesis in transgenic Zebra fish model.
In the neurogenesis wing of our laboratory we are studying the role of endocannabinoid and its receptors in neuroprotection and neurogenesis using animal models of ischemia (MCAO model of ischemic stroke and hind-limb ischemia in rodents). We are studying the role CB1 cannabinoid receptor-mediated nitric oxide production in the regulation of matrix metalloprotease 9 activity in relation to ischemia-induced neuronal damage and subsequent angiogenesis and neurogenesis. In a related project we are investigating the role of endocannabinoid anandamide and CB1 receptor in rat brain hippocampal neurogenesis under normoxic and ischemic condition.
Click on Thumbnails individually to see full Figure
McCollum L., Howlett AC and Mukhopadhyay S. (2007) Anandamide-mediated CB1/CB2 receptor-independent NO production in rabbit aortic endothelial cells. J Pharmacol Exp Ther. 321: 930-937.
Anavi-Goffer S, Fleischer D, Hurst DP, Lynch DL, Barnett-Norris J, Shi S, Lewis DL, Mukhopadhyay S, Howlett AC, Reggio PH, Abood ME Helix 8 Leu in the CB1 cannabinoid receptor contributes to selective signal transduction mechanisms. J Biol Chem.282: 25100-13,2007
Chi, SL., Wahl, ML., Mowery, YV., Shan, S., Mukhopadhyay, S., Hildebrandt, S., Kenan, DJ., Lipes, BD., Johnson, CE., Marusich, M.,Capaldi,RA., Dewhirst, MW and Pizzo SV Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1Fo ATP synthase Cancer Research 67: 4716-24, 2007
Mukhopadhyay, S. and Tulis, D.A. Endocannabinoid Regulation of Matrix metalloproteinases: Implications in Ischemic Stroke. Cardiovasc. Hematol. Agents Med. Chem. (in press).
Howlett, AC., Mukhopadhyay, S and Derek Norford (2007) Endocannabinoids and Reactive Nitrogen and Oxygen Species in Neuropathologies J. Neuroimmune Pharmacology (in press).
Jackson EB, Mukhopadhyay S, Tulis DA Pharmacologic modulators of soluble guanylate cyclase/cyclic guanosine monophosphate in the vascular system - from bench top to bedside. Curr. Vasc. Pharmacol. 5: 1-14, 2007
Niehaus JL, Liu Y, Wallis KT, Egertova M, Bhartur SG, Mukhopadhyay S, Shi S,He H, Selley DE, Howlett AC, Elphick MR, Lewis DL . CB1 cannabinoid receptor activity is modulated by the interacting protein CRIP1a. Mol Pharmacol 72:1557-66,2007
Mukhopadhyay S., Das, S., Williams EA., Moore, D., Jones JD., Zahm, DS., Ndengele, MM., Lechner, AJ and Howlett, AC.Lipopolysaccharide and cyclic AMP regulation of CB(2) cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages. J. Neuroimmunol. 181:82-92, 2006
Mukhopadhyay, S and Howlett, AC Chemically Distinct Ligands Promote Differential CB1 Cannabinoid Receptor-Gi Protein Interactions Mol Pharmacol 67: 2016-24, 2005
Mukhopadhyay, S., Shim, JY., Assi, AA., Norford, D andHowlett, AC. CB1 cannabinoid receptor-G protein association: A possible mechanism for differential signaling. Chem Phys. Lipids.121: 91-109, 2002
Mukhopadhyay, S, Chapnick, B and Howlett AC Ananadamide-induced vasorelaxation in rabbit aortic rings has two components: G protein-dependent and G protein-independent American J Physiol (Heart and Circulatory) 282: H2046-H2054, 2002
Mukhopadhyay, S. and Howlett, A.C. CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. Eur. J. Biochem., 268:499-505, 2001.
Mukhopadhyay, S. McIntosh, H., Houston DB and. Howlett, AC. Cannabinoid receptor-derived juxtamembrane C-terminal peptide uncouples receptor-G protein interaction. Mol Pharmacol 57: 162-170, 2000
Mukhopadhyay, S. . Cowsik, S., Welsh, WJ and Howlett, AC. Regulation of Gi by the CB1 cannabinoid receptor C-terminal juxtamembrane region: Structural requirement determined by peptide analysis. Biochemistry 38: 3447-3455, 1999