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Cannabinoid CB? receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.

ABSTRACT: Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated. In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated. To assess the function of cannabinoid CB2 receptors, skin excisional BALB/c mice were treated with either the cannabinoid CB2 receptor selective agonist, GP1a, or antagonist, AM630. Skin fibrosis was assessed by histological analysis and profibrotic cytokines were determined by immunohistochemistry, immunofluorescence staining, reverse transcription?quantitative polymerase chain reaction and immunoblotting in these animals. GP1a decreased collagen deposition, reduced the levels of transforming growth factor (TGF)??1, TGF?? receptor I (T?RI) and phosphorylated small mothers against decapentaplegic homolog 3 (P?Smad3), but elevated the expression of its inhibitor, Smad7. By contrast, AM630 increased collagen deposition and the expression levels of TGF??1, T?RI and P?Smad3. These results indicated that cannabinoid CB2 receptors modulate fibrogenesis and the TGF??/Smad profibrotic signaling pathway during skin wound repair in the mouse.

SUBMITTER: Li SS

PROVIDER: S-EPMC4805070 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Cannabinoid CB₂ receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.

Li Shan-Shan SS Wang Lin-Lin LL Liu Min M Jiang Shu-Kun SK Zhang Miao M Tian Zhi-Ling ZL Wang Meng M Li Jiao-Yong JY Zhao Rui R Guan Da-Wei DW

Molecular medicine reports 20160302 4

Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated. In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated. To assess the function of cannabinoid CB2 receptors, skin excisional BALB/c mice were treated with either the cannabinoid CB2 receptor selective agonist, GP1a, or antagonist, AM630. Skin fibrosis was ...[more]

PMID: 26935001

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Project description:Receptor internalization increases the flexibility and scope of G protein-coupled receptor (GPCR) signaling. CB(1) and CB(2) cannabinoid receptors undergo internalization after sustained exposure to agonists. However, it is not known whether different agonists internalize CB(2) to different extents. Because CB(2) is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classic, aminoalkylindole, bicyclic, cannabilactone, iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB(1) and CB(2) trafficking. Our most striking finding was that (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212-2) (and other aminoalkylindoles) failed to promote CB(2) receptor internalization, whereas 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP55,940) robustly internalized CB(2) receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB(2) internalization. Despite these differences in internalization, both compounds activated CB(2) receptors as measured by extracellular signal-regulated kinase 1/2 phosphorylation and recruitment of β-arrestin(2) to the membrane. In contrast, whereas CP55,940 inhibited voltage-gated calcium channels via CB(2) receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. On the basis of the differences we found between these two ligands, we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB(2) ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB(2) receptors and suggest that different classes of CB(2) ligands may produce diverse physiological effects, emphasizing that each class needs to be separately evaluated for therapeutic efficacy.

Dataset Information

Cannabinoid CB? receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.

Publications

Cannabinoid CB₂ receptors are involved in the regulation of fibrogenesis during skin wound repair in mice.

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