Pharmacology, Signaling and Physiological Relevance of the G Protein-coupled Receptor 55

Abstract

According to The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), ∼70 million European adults have consumed cannabis on at least one occasion. Cannabis consumption leads to a variety of psychoactive effects due to the presence of the constituent Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Δ⁹-THC interacts with the endocannabinoid system (ECS), which consists of the seven transmembrane spanning (7TM)/G protein-coupled receptors (GPCRs) CB₁ and CB₂, their respective ligands (endocannabinoids), and enzymes involved in their biosynthesis and degradation. This system plays a critical role in many physiological processes such as learning and memory, appetite control, pain sensation, motor coordination, lipogenesis, modulation of immune response, and the regulation of bone mass. Therefore, a huge effort has been spent trying to fully elucidate the composition and function of the ECS. The G protein-coupled receptor 55 (GPR55) was recently proposed as a novel component of this system; however, its classification as a cannabinoid receptor has been significantly hampered by its complex pharmacology, signaling, and cellular function. GPR55 is phylogenetically distinct from the traditional cannabinoid receptors, but in some experimental paradigms, it is activated by endocannabinoids, phytocannabinoids, and synthetic cannabinoid ligands. However, the most potent compound appears to be a lysophospholipid known as lysophosphatidylinositol (LPI). Here, we provide a comprehensive evaluation of the current pharmacology and signaling of GPR55 and review the proposed role of this receptor in a number of physiological and pathophysiological processes.

Introduction

Cannabis sativa, also known as marijuana, is a widespread illegal drug and a well-known medicinal plant (Watson et al., 2000), which contains ∼ 60 phytocannabinoids, some of which are bioactive (Mechoulam & Gaoni, 1965). The most-studied phytocannabinoid is Δ⁹-tetrahydrocannabinol (Δ⁹-THC), which mediates most of the psychotropic properties of C. sativa (Hall & Solowij, 1998).

Before the 1980s, it was thought that cannabinoids produced their effects by nonspecifically interfering with cell membranes (Pertwee, 2006); however, subsequent work led to the cloning and isolation of specific cannabinoid receptors, termed CB₁ and CB₂, which belong to the 7TM/GPCR super family (Matsuda et al., 1990, Munro et al., 1993). CB₁ is the most widely expressed GPCR in the brain and found primarily at presynaptic nerve terminals where it inhibits neurotransmitter release (Pertwee, 1997). CB₂ is predominantly expressed in the immune system and modulates cytokine production and immune cell migration (Kurihara et al., 2006). N-arachidonoylethanolamine (Anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), the two major endogenous cannabinoids, are synthesized on demand and bind to both CB₁ and CB₂ (Hillard and Jarrahian, 2003, Matias and Di, 2007). Cannabinoid receptors, endocannabinoids, and the enzymes involved in their metabolism comprise the mammalian endocannabinoid system (ECS). The ECS is implicated in a variety of physiological functions, for example, the reduction of neurotransmitter release from presynaptic neurons (Cinar et al., 2008) and enhancement of de novo lipogenesis in the liver are mediated via CB₁ (Osei-Hyiaman et al., 2005), whereas bacteria-induced immune responses (Miller & Stella, 2008) and bone mass are regulated by CB₂ (Ofek et al., 2006).

However, it appeared that this picture was somewhat oversimplified, as CB₁ and CB₂ knockout (KO) animals still retained a variety of cannabinoid effects, suggesting the presence of novel cannabinoid targets in the body (Begg et al., 2005, Haller et al., 2004, Jarai et al., 1999, Ledent et al., 1999, Zimmer et al., 1999). Other targets have been identified with sensitivity to endocannabinoids, such as the transient receptor potential cation channel 1 (TRPV1; Smart et al., 2000) and, more recently, the orphan G protein-coupled receptor 55 (GPR55; Baker et al., 2006). GPR55 has received significant interest as a putative CB₃ receptor due to early patent literature, suggesting it was activated by cannabinoid ligands (Brown and Wise, 2001, Drmota et al., 2004).