Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain

Abstract

Neuroinflammation plays a critical role in the pathological process of multiple neurological disorders and pathological pain conditions. GPR109A, a Gi protein-coupled receptor, has emerged as an important therapeutic target for controlling inflammation in various tissues and organs. In this review, we summarized current data about the role of GPR109A in neuroinflammation. Specifically, we focused on the pharmacological features of GPR109A and signaling pathways used by GPR109A to ameliorate neuroinflammation and symptoms in Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and pathological pain conditions.

Keywords: HCAR2; lupus; neuroinflammation; neuropathic; niacin; nociception; synaptic; β-hydroxybutyrate; cytokines.

Figure 1

Molecular signaling pathways used by GPR109A to attenuate spinal neuroinflammation and chronic pain induced by SLE in mice. Mice with chronic pain caused by SLE have increased p38 MAPK activity and production of IL-1β and IL18 in the spinal dorsal horn. IL-18 enhances glutamate release from the primary afferent terminals (presynaptic terminals), while IL-1β reduces glial glutamate uptake by suppressing glial glutamate transporter activity. Activation of microglial GPR109A attenuates glutamatergic synaptic activity and chronic pain by suppressing p38 MAPK activity and production of IL-1β and IL-18. AMPA-R: Aminomethylphosphonic acid receptor; Gln: glutamine; Glu: glutamate; GluT: glutamate transporter; IL: interleukin; MAPK: mitogen-activated protein kinase; NMDA-R: N-methyl-D-aspartic acid receptor; SLE: systemic lupus erythematosus.