[Function of glial G-protein coupled receptors]

Abstract

G-protein coupled receptors (GPCRs) form the largest superfamily of membrane proteins. About 50% of medicines are thought to target GPCRs. We recently developed a novel strategy to screen GPCRs that are highly or selectively expressed in particular cells of the brain. Since recent literature suggests causative roles of glial cell dysfunction in many neuropsychiatric disorders, we first characterized GPCRs expressed in cultured astrocytes and neural progenitor cells (NPCs) using the method. Among approximately 300 GPCRs expressed in the adult mouse brain, we found that type 2 neurotensin receptor (Ntsr2) was abundantly expressed in cultured astrocytes. In situ hybridization of Ntsr2 and co-immunostaining of GFAP confirmed that the molecule was expressed in astrocytes of the adult mouse brain. Mice lacking Ntsr2 showed altered emotional behaviors. Application of a Ntsr2 agonist modified the behavior of wild type mice. In NPCs, PACAP receptor (PAC1) was identified as one of the highly expressed GPCRs. Previously the PACAP/PAC1 system was reported to induce differentiation of NPCs. We observed that PACAP and PAC1 were co-localized in NPCs of the mouse embryonic cortex and that activation of the PACAP/PAC1 system potentiated growth factor-induced proliferation of the glial progenitors. Furthermore, VPAC2, a structurally related GPCR to PAC1, was detected in reactive astrocytes in vivo. These observations suggest potential roles of Ntsr2, PAC1 and VPAC2 in the development, expression and maintenance of the brain function. Further study on glial GPCRs should provide important information for the role of astrocytes in the processing of neural information.