CCK1R and CCK2R belong to the family of G-protein-coupled receptors (GPCRs). The two genes share only 50% sequence homology, mostly in domains characteristic of GPCRs and in sequence signatures that are required for receptor activation, which might explain their differences in affinity for ligands
[3]. Though there remain some controversies, CCK2R can be generally associated with Gq protein, and to a lesser extent with Gi, contrary to CCK1R which is associated with Gs protein
[4]. The activated Gq pathway passes through phospholipase C beta (PLCβ), which hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol-trisphosphate (IP3), leading to the release of intracellular Ca
2+ stores into the cytoplasm, and to diacylglycerol (DAG), leading to the activation of protein kinase C (PKC). Ca
2+ is a major effector of neuronal function, involved in neurotransmitter release and membrane excitability. It has been shown that PKC can play a crucial role in the regulation of GPCRs
[5]. GPCRs are comprised of seven α-helical transmembrane domains, an extracellular
N terminus with three extracellular loops, and an intracellular C terminus with three intracellular loops. GPCRs are a major class of proteins that are potentially involved in pain transmission and so, represent a preferred therapeutic target for novels analgesics
[6]. For example, serotonin, apelin, dopamine, GABA
B, opioid receptors and the recently clinically-implicated angiotensin II type 2 receptor (AT2R), all use signaling that passes through the GPCR family proteins and have roles in pain modulation
[6][7].