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

JCI Insight. 2019 Feb 21;4(4):e122947. doi: 10.1172/jci.insight.122947.


GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.

Keywords: Endocrinology; G-protein coupled receptors; Gastroenterology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / physiology*
  • Aged
  • Aged, 80 and over
  • Animals
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Antagonists / pharmacology
  • Carcinoma, Mucoepidermoid / pathology*
  • Carcinoma, Mucoepidermoid / radiotherapy
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Self Renewal / drug effects
  • Cell Self Renewal / physiology
  • Down-Regulation
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Female
  • Glycoproteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Receptors, Cannabinoid / genetics
  • Receptors, Cannabinoid / metabolism*
  • Saliva / chemistry
  • Saliva / metabolism
  • Salivary Gland Neoplasms / pathology*
  • Salivary Gland Neoplasms / radiotherapy
  • Salivation / drug effects
  • Salivation / physiology*
  • Submandibular Gland / drug effects
  • Submandibular Gland / metabolism
  • Submandibular Gland / pathology


  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • GPR55 protein, human
  • GPR55 protein, mouse
  • Glycoproteins
  • Receptors, Cannabinoid