GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation

Korchynska, Solomiia; Lutz, Mirjam I.; Borók, Erzsébet; Pammer, Johannes; Cinquina, Valentina; Fedirko, N. V.; Irving, Andrew J.; Harkany, Tibor; Keimpema, Erik

doi:10.1172/jci.insight.122947

Cited by 4 publications

(4 citation statements)

References 60 publications

(71 reference statements)

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“…Our finding that CB1 protein expression is chiefly neuronal/ axonal in nature contrasts with previous studies that reported CB1 protein in multiple cell types including acini and ductal epithelial cells 17 , 21 , 24 . Because those studies made use of rat 16 , 24 , or piglet 21 , neither was in a position to validate expression patterns in knockout animals, though it is possible that CB1 expression varies by species. Our immunohistochemical findings of CB1 and FAAH expression within the submandibular gland, and NAPE-PLD in myoepithelial cells, suggest the following circuit: NAEs are synthesized locally in myoepithelial cells, then act on CB1 receptors expressed in parasympathetic axons, after which they are broken down locally in non-ductal acinar cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…As exocrine glands that are under opposing parasympathetic/sympathetic control, salivary and lacrimal glands have much in common, including regulation by the same brainstem nucleus (superior salivatory nucleus) 1 , 15 . Though potential salivary gland roles for some of these receptors have been reported, such as Korchinsky et al that implicates GPR55 in salivary gland development 16 , the remaining receptors have seen limited (CB1/CB2) 17 – 24 or no study in this context. The current project was conceived to test whether and how CB1 receptors might regulate salivary gland function.…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid CB1 receptors regulate salivation

Andreis

Billingsley

Shirazi

et al. 2022

Sci Rep

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Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren’s syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cannabinoid CB1 receptors regulate salivation

Andreis

Billingsley

Shirazi

et al. 2022

Sci Rep

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“…Regulate cell proliferation and function 94) γδT cell Suppress T cell homing and accumulation in the small intestine 9,62) (Fig. 4).…”

Section: Salivary Glandsmentioning

confidence: 99%

“…92,93) GPR55 also controls the functional differentiation of self-renewing epithelial progenitors for salivation. 94) At the cellular level, GPR55 couples with Gα12/13 and induces inhibition of neurite outgrowth. 82) 5.…”

Section: Gpr55 Has Multiple Rolesmentioning

confidence: 99%

The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field

Takagi

Nishikado

Omi

et al. 2022

Biological & Pharmaceutical Bulletin

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Lysophospholipids are phospholipids with only one fatty acid. During the past two decades, it has become apparent that lysophospholipids are not merely degradation products but have various physiological and pathological functions in vivo via G protein-coupled receptor (GPCR)-type receptors. These include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylinositol/lysophosphatidylglucose (LPI/LPtdGlc), and lysophosphatidylserine (LysoPS). This review focuses on identifying the functions of the receptors, enzymes, transporters, and carrier proteins required for these four lysophospholipids to function as lipid mediators. We also note that many of advances in this field have been made by Japanese pharmaceutical scientists.

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Druggable Lysophospholipid Signaling Pathways

Yanagida

Valentine

2020

Druggable Lipid Signaling Pathways

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GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation

Cited by 4 publications

References 60 publications

Cannabinoid CB1 receptors regulate salivation

Cannabinoid CB1 receptors regulate salivation

The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field

Druggable Lysophospholipid Signaling Pathways

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