GPR55, a G-Protein Coupled Receptor for Lysophosphatidylinositol, Plays a Role in Motor Coordination

Chia-Shan Wu,Ken Mackie,James Wager-Miller,Heather Bradshaw,Hongmei Chen,Hui-Chen Lu,Corinne Spencer,Alex Straiker,Chris P Jew,Hao Sun,Jie Zhu,Ya-Ping Tang

doi:10.1371/journal.pone.0060314

Abstract

The G-protein coupled receptor 55 (GPR55) is activated by lysophosphatidylinositols and some cannabinoids. Recent studies found prominent roles for GPR55 in neuropathic/inflammatory pain, cancer and bone physiology. However, little is known about the role of GPR55 in CNS development and function. To address this question, we performed a detailed characterization of GPR55 knockout mice using molecular, anatomical, electrophysiological, and behavioral assays. Quantitative PCR studies found that GPR55 mRNA was expressed (in order of decreasing abundance) in the striatum, hippocampus, forebrain, cortex, and cerebellum. GPR55 deficiency did not affect the concentrations of endocannabinoids and related lipids or mRNA levels for several components of the endocannabinoid system in the hippocampus. Normal synaptic transmission and short-term as well as long-term synaptic plasticity were found in GPR55 knockout CA1 pyramidal neurons. Deleting GPR55 function did not affect behavioral assays assessing muscle strength, gross motor skills, sensory-motor integration, motor learning, anxiety or depressive behaviors. In addition, GPR55 null mutant mice exhibited normal contextual and auditory-cue conditioned fear learning and memory in a Pavlovian conditioned fear test. In contrast, when presented with tasks requiring more challenging motor responses, GPR55 knockout mice showed impaired movement coordination. Taken together, these results suggest that GPR55 plays a role in motor coordination, but does not strongly regulate CNS development, gross motor movement or several types of learned behavior.

Highlights

The observation that cannabinoids produce effects independent of CB1 and CB2 cannabinoid receptors motivated the search for additional cannabinoid receptors
Using quantitative PCR we found that G-protein coupled receptor 55 (GPR55) mRNA was expressed in mouse brain in the following order: striatum.hippocampus.forebrain.cortex.cerebellum (Fig. 1A)
We found no alterations in the levels of the 2arachidonoyl glycerol (2-AG) degrading enzymes alpha/beta-hydrolase domain containing 6 enzyme (ABDH6) and monoacyl glycerol lipase (MGL), the 2-AG synthesizing enzymes diacylglycerol lipase alpha and beta (DGLa and DGLb), nor the AEA degrading enzyme fatty acid amide hydrolase (FAAH) (Table 1)

Summary

Introduction

The observation that cannabinoids produce effects independent of CB1 and CB2 cannabinoid receptors motivated the search for additional cannabinoid receptors (reviewed in [1]). The identification of G-protein coupled receptor 55 (GPR55) as a potential cannabinoid receptor generated significant interest [2,3]. Its potential assignment as a cannabinoid receptor was based on its potent activation by a subset of cannabinoid ligands [1,4,5,6]. Synthetic cannabinoid ligands reported to activate GPR55 include the CB2-preferring aminoalkylindole, JWH015, the CB1 inverse agonists, SR141716A and AM251, and the metabolically stable anandamide analog, methanandamide. Lysophosphatidylinositols (LPI) have been identified as endogenous ligands for GPR55 [7]. GPR55 binds and is activated by an impressive array of structurally diverse ligands. All well-characterized and frequently used GPR55 ligands interact with other receptors, channels, and/or signaling molecules at concentrations similar to those that activate or antagonize GPR55

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Conclusion