title: Cannabinoid receptor-mediated translocation of NO-sensitive guanylyl cyclase and production of cyclic GMP in neuronal cells.
abstract: Cannabinoid agonists regulate NO and cyclic AMP production in N18TG2 neuroblastoma cells, leading to the hypothesis that neuronal cyclic GMP production could be regulated by CB(1) cannabinoid receptors. NO (nitric oxide)-sensitive guanylyl cyclase (GC) is a heterodimeric cytosolic protein that mediates the down-stream effects of NO. Genes of proteins in the cyclic GMP pathway (alpha(1), alpha(2), and beta(1) subunits of NO-sensitive GC and PKG1, but not PKG2) were expressed in N18TG2 cells, as was the CB(1) but not the CB(2) cannabinoid receptor. Stimulation of N18TG2 cells by cannabinoid agonists CP55940 and WIN55212-2 increased cyclic GMP levels in an ODQ-sensitive manner. GC-beta(1) in membrane fractions was increased after 5 or 20 min stimulation, and was significantly depleted in the cytosol by 1h. The cytosolic pool of GC-beta(1) was replenished after 48 h of continued cannabinoid drug treatment. Translocation of GC-beta(1) from the cytosol was blocked by the CB(1) antagonist rimonabant (SR141716) and by the Gi/o inactivator pertussis toxin, indicating that the CB(1) receptor and Gi/o proteins are required for translocation. Long-term treatment with rimonabant or pertussis toxin reduced the amount of GC-beta(1) in the cytosolic pool. We conclude that CB(1) receptors stimulate cyclic GMP production and that intracellular translocation of GC from cytosol to the membranes is intrinsic to the mechanism and may be a tonically active or endocannabinoid-regulated process.
authors: Neuroscience of Drug Abuse Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA.
authors: Jenelle D
authors: JD
authors: Jones
authors: Skyla T
authors: ST
authors: Carney
authors: Kent E
authors: KE
authors: Vrana
authors: Derek C
authors: DC
authors: Norford
authors: Allyn C
authors: AC
authors: Howlett
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma; D009569:Nitric Oxide / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077285:Rimonabant; D013997:Time Factors
chemical_list: D002186:Cannabinoids; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D009569:Nitric Oxide; D037342:Pertussis Toxin; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000077285:Rimonabant
references: Biochim Biophys Acta. 1993 Jun 30;1177(3):299-306
references: 8100714
references: Biochem Pharmacol. 2000 Nov 1;60(9):1315-23
references: 11008125
references: Neuroscience. 1994 Dec;63(3):637-52
references: 7898667
references: Life Sci. 1995;56(23-24):1941-7
references: 7776817
references: Mol Pharmacol. 1995 Aug;48(2):184-8
references: 7544433
references: Biochem J. 1996 Jun 15;316 ( Pt 3):977-84
references: 8670178
references: Biochem Pharmacol. 1996 Sep 27;52(6):819-27
references: 8781498
references: Biochem Biophys Res Commun. 1996 Oct 3;227(1):281-8
references: 8858137
references: Biochem Biophys Res Commun. 1997 Apr 7;233(1):207-10
references: 9144424
references: Neuroscience. 1998 Mar;83(2):393-411
references: 9460749
references: Neuroscience. 1998 Jan;82(1):255-65
references: 9483518
references: J Biol Chem. 1998 Aug 7;273(32):20029-35
references: 9685341
references: Brain Res. 1999 Jul 10;834(1-2):128-35
references: 10407101
references: J Biol Chem. 2004 Nov 5;279(45):46946-53
references: 15347653
references: J Biol Chem. 2004 Nov 19;279(47):49346-54
references: 15381706
references: Cell Signal. 2005 Apr;17(4):407-13
references: 15601619
references: J Biol Chem. 2005 Jan 21;280(3):2186-96
references: 15509556
references: Biochem Pharmacol. 2005 Jun 15;69(12):1705-13
references: 15885656
references: Pharmacol Biochem Behav. 2005 Jun;81(2):224-38
references: 15935454
references: Pharmacol Biochem Behav. 2005 Jun;81(2):248-62
references: 15935456
references: Eur J Neurosci. 2001 Feb;13(3):539-44
references: 11168561
references: Biochim Biophys Acta. 2001 May 28;1539(1-2):16-27
references: 11389965
references: Brain Res. 2001 Jul 13;907(1-2):54-60
references: 11430885
references: Trends Pharmacol Sci. 2001 Nov;22(11):565-72
references: 11698100
references: J Biol Chem. 2001 Nov 30;276(48):44647-52
references: 11572861
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Nat Cell Biol. 2002 Apr;4(4):307-11
references: 11887187
references: J Biol Chem. 2002 May 10;277(19):16412-8
references: 11867632
references: Pharmacol Rev. 2002 Jun;54(2):161-202
references: 12037135
references: J Neurosci. 2002 Oct 15;22(20):8961-70
references: 12388603
references: Chem Phys Lipids. 2002 Dec 31;121(1-2):91-109
references: 12505694
references: Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H669-78
references: 12676772
references: J Biol Chem. 2003 Nov 14;278(46):46188-94
references: 12952947
references: Mol Endocrinol. 2004 Feb;18(2):458-70
references: 14630997
references: Br J Pharmacol. 2004 May;142(1):9-19
references: 15100161
references: Neurochem Int. 2004 Nov;45(6):833-43
references: 15312977
references: J Pharmacol Exp Ther. 2004 Oct;311(1):256-64
references: 15187170
references: Neuropharmacology. 2004;47 Suppl 1:345-58
references: 15464149
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Mol Pharmacol. 1984 Nov;26(3):532-8
references: 6092901
references: Mol Pharmacol. 1986 Mar;29(3):307-13
references: 2869405
references: J Neurosci Res. 1987;17(3):291-7
references: 3037096
references: J Neurosci. 1991 Feb;11(2):563-83
references: 1992016
references: Neuroscience. 1992;48(3):655-68
references: 1376455
references: Pharmacol Biochem Behav. 2005 Jun;81(2):239-47
references: 15936805
references: Bull Exp Biol Med. 2004 Dec;138(6):550-3
references: 16134810
references: Behav Pharmacol. 2005 Sep;16(5-6):275-96
references: 16148435
references: Mol Pharmacol. 2005 Oct;68(4):1133-41
references: 16024662
references: J Pharmacol Exp Ther. 2007 Jun;321(3):930-7
references: 17379772
references: Mol Pharmacol. 1993 Sep;44(3):498-503
references: 8371711