Role of GPR39 in Neurovascular Homeostasis and Disease

Abstract

GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system. We further discuss its recognized role in neurovascular, neurological, and neuropsychiatric disorders.

GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment

“…GPR39 has been proposed to play a role in multiple homeostatic processes in the brain, including the balance between neuronal excitation and inhibition, vasodilation and vasoconstriction, and pro- and anti-inflammatory pathways ( Xu et al, 2021 ). GPR39 has also been implicated in a variety of neurological and neuropsychiatric disorders, including AD, depression, anxiety, and seizures ( Laitakari et al, 2021 ).…”

“…Finally, while mechanistic inquiries are beyond the scope of the current study, the data presented here is the first description of cognitive impairment in GPR39 KO mice. As discussed in our review article ( Xu et al, 2021 ), specific cellular mediators are being actively investigated and will be pursued in future studies.…”

“…We recently reported that the G protein-coupled receptor 39 (GPR39) is a dual-ligand receptor regulated by AA-derived oxylipins with opposing actions on inflammation and microvascular tone ( Xu et al, 2021 ; Alkayed et al, 2022 ). GPR39 is a member of the ghrelin family of G protein-coupled receptors (GPCRs) that has recently been implicated in VCI ( Davis et al, 2021a ).…”

Molecular Mechanisms of Cerebrovascular Diseases

“…A new therapeutic target in cerebrovascular disease, GPR39 (a member of the ghrelin family of G-protein coupled receptors), is reviewed by Xu et al [13]. They discussed its role in brain and neurovascular homeostasis by maintaining excitatory/inhibitory tone in neural circuits as well as by controlling vascular and inflammatory tone.…”

Data_Sheet_1.pdf

“…We recently reported that the G protein-coupled receptor 39 (GPR39) is a dual-ligand receptor regulated by AAderived oxylipins with opposing actions on inflammation and microvascular tone (Xu et al, 2021;Alkayed et al, 2022). GPR39 is a member of the ghrelin family of G proteincoupled receptors (GPCRs) that has recently been implicated in VCI (Davis et al, 2021a).…”