Advances in Neurobiology and Pharmacology of GPR12

Abstract

GPR12 is a G protein-coupled orphan receptor genetically related to type 1 and type 2 cannabinoid receptors (CB 1 and CB 2 ) which are ancient proteins expressed all over the body. Both cannabinoid receptors, but especially CB 1 , are involved in neurodevelopment and cognitive processes such as learning, memory, brain reward, coordination, etc. GPR12 shares with CB 1 that both are mainly expressed into the brain. Regrettably, very little is known about physiology of GPR12. Concerning its pharmacology, GPR12 seems to be endogenously activated by the lysophospholipids sphingosine-1-phosphate (S1P) and sphingosyl-phosphorylcholine (SPC). Exogenously, GPR12 is a target for the phytocannabinoid cannabidiol (CBD). Functionally, GPR12 seems to be related to neurogenesis and neural inflammation, but its relationship with cognitive functions remains to be characterized. Although GPR12 was initially suggested to be a cannabinoid receptor, it does not meet the five criteria proposed in 2010 by the International Union of Basic and Clinical Pharmacology (IUPHAR). In this review, we analyze all the direct available information in PubMed database about expression, function, and pharmacology of this receptor in central nervous system (CNS) trying to provide a broad overview of its current and prospective neurophysiology. Moreover, in this mini-review we highlight the need to produce more relevant data about the functions of GPR12 in CNS. Hence, this work should motivate further research in this field.

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

“…In addition to the two well-characterized G protein-coupled receptors CB1 and CB2, several orphan G protein-coupled receptors or GPRs have been described in the last years to be putative cannabinoid receptors, such as GPR3, GPR6, GPR12, GPR18, and GPR55 [ 173 , 174 , 175 ]. GPR3, GPR6, and GPR12 have a close phylogenetic affinity and conserve specific sequences with the cannabinoid receptors CB1 and CB2 [ 173 ].…”

“…An increased hippocampal expression was also observed for GPR6 in the 3 × Tg AD mouse model, where GPR6 modulates the neuroprotective effect of the complement protein C1q against Aβ [ 180 ]. GPR18 and GPR55 despite, GPR3, GPR6, and GPR12, have low homology with CB1 and CB2 [ 175 ]. GPR55 has opposite signaling pathways from CB1/CB2 since it is coupled to Gα 12,13 , and its activation is linked to an outflow of calcium from intracellular stores via phospholipase C [ 181 ].…”

GPR12 inhibits migration and promotes apoptosis in esophageal cancer and hypopharyngeal cancer cells

“…These observations clearly demonstrated that GPR12 could inhibit the migration of Eca109 and FaDu cells through inhibiting EMT progression, although the underlying mechanism remained to be elucidated. There have been numerous studies on GPR12 in neurology, 26 however, few such studies focus on tumors. Our research shows that GPR12 could be a potential therapeutic target for regulating EMT and cancer migration.…”

The Periaqueductal Gray and Its Extended Participation in Drug Addiction Phenomena

“…Other putative receptors strongly associated with the endocannabinoid system (e.g., GPR12, GPR18, and GPR55) have also been associated with multiple cognitive processes such as learning and memory and food intake. [183][184][185][186][187][188].…”