The therapeutic potential of orphan GPCRs, GPR35 and GPR55

Abstract

The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it’s not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands—the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles.

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…Lastly, the potential actions of kynurenic acid on the Aryl Hydrocarbon Receptors (Opitz et al ) or the orphan G‐protein‐coupled receptor G‐protein‐coupled receptor‐35 (GPR35) (Wang et al ; Mackenzie and Milligan ; Shore and Reggio, ) were not considered by Stone () since kynurenines had not yet been linked with their activity. AHRs have received little attention in the CNS since primary interest has been in their role in immune system cells and the regulation of kynurenine pathway activation in tolerogenesis.…”

Receptor selectivity between the G proteins Gα 12 and Gα 13 is defined by a single leucine‐to‐isoleucine variation

“…An interesting case in point is G protein-coupled receptor 35 (GPR35) (20). Although officially an orphan receptor, in that suggestions of its endogenous activator or activators remain controversial (20)(21)(22)(23)(24), a wide range of surrogate agonists are available (20,25). Although coupling to Ga 12 /Ga 13 is well established, the basis of potential selectivity in so doing is not.…”

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…The a subunits are divided into 4 families: Ga q/11 , Ga s , Ga i/o , and Ga 12/13 (7). GPCRs regulate almost all known cellular events and physiologic processes; therefore, not surprisingly, they represent major pharmaceutical targets; .60% of all drugs target GPCRs (8).…”