Signaling and functions of G-protein-coupled receptor 3 in cerebellar granular neurons

G-protein-coupled receptor 3 (GPR3) is a member of the class A rhodopsin-type GPCR family and is highly expressed in various neurons. A unique feature of GPR3 is its ability to constitutively activate the Gαs protein without the addition of ligands, which results in the elevation of the basal level of intracellular cAMP. During the development of the cerebellum, GPR3 expression is upregulated in cerebellar granular neurons (CGNs) and maintained thereafter. In our previous studies, we showed that the intrinsic expression of GPR3 in CGNs is highly associated with neurite outgrowth, neurite differentiation, and neuronal survival. Recently, we have focused on the possible signaling pathways associated with GPR3-mediated neurite outgrowth in CGNs. Interestingly, GPR3-mediated neurite outgrowth is mediated by not only PKA-dependent signaling pathways but also PI3K-mediated signaling pathways. Moreover, the Gβγ-mediated signaling pathway is involved in GPR3-mediated neurite outgrowth. These results suggested that neural expression of GPR3 stimulates multiple downstream signaling pathways, contributing to the maintenance of homeostasis in neurons. Further precise analyses of constitutively active GPCRs may help in unveiling novel neuronal functions.