Fig 6. GPR4 signaling pathways and action modes of the imidazopyridine compound and psychosine as the GPR4 modulator and antagonist.

Extracellular protons induce GPR4 activation through histidine residues and subsequent activation of G protein/effector systems, i.e., G_s/cAMP system and G₁₃/Rho system, resulting in the mRNA expression of adhesion molecules and SRE transcriptional activation, respectively. Similarly to other GPCRs, GPR4 is desensitized by its internalization in response to extracellular acidification. Both imidazopyridine compound and psychosine inhibit the proton/GPR4 function but by different action modes with respect to the histidine susceptibility. See text more detail.