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Molecular Pharmacology

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Research ArticleArticle

N-Arachidonyl Glycine Does Not Activate G Protein–Coupled Receptor 18 Signaling via Canonical Pathways

Van B. Lu, Henry L. Puhl III and Stephen R. Ikeda
Molecular Pharmacology January 2013, 83 (1) 267-282; DOI: https://doi.org/10.1124/mol.112.081182
Van B. Lu
Section on Transmitter Signaling, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Henry L. Puhl III
Section on Transmitter Signaling, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Stephen R. Ikeda
Section on Transmitter Signaling, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Abstract

Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the Gαi/o protein–coupled receptor 18 (GPR18). However, a high-throughput β-arrestin–based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18:12328). To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors. GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Cav2.2) calcium channels was examined. Proper expression and trafficking of receptor were confirmed by the “rim-like” fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18-expressing cells. Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100:1147). Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents. Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins. Other downstream effectors of Gαi/o-coupled receptors, G protein–coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling. Furthermore, GPR18 did not couple to other G proteins tested: Gαs, Gαz, and Gα15. These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies.

Footnotes

  • This research was supported by the Intramural Research Program of the National Institutes of Health [National Institute on Alcohol Abuse and Alcoholism]

  • dx.doi.org/10.1124/mol.112.081182.

  • ↵Embedded ImageThis article has supplemental material available at mol.aspetjournals.org.

  • Received July 13, 2012.
  • Accepted October 25, 2012.
  • U.S. government work not protected by U.S. copyright.
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Molecular Pharmacology: 83 (1)
Molecular Pharmacology
Vol. 83, Issue 1
1 Jan 2013
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Research ArticleArticle

Lack of GPR18 Activation by NAGly

Van B. Lu, Henry L. Puhl and Stephen R. Ikeda
Molecular Pharmacology January 1, 2013, 83 (1) 267-282; DOI: https://doi.org/10.1124/mol.112.081182

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Research ArticleArticle

Lack of GPR18 Activation by NAGly

Van B. Lu, Henry L. Puhl and Stephen R. Ikeda
Molecular Pharmacology January 1, 2013, 83 (1) 267-282; DOI: https://doi.org/10.1124/mol.112.081182
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