An interaction between PAC1 receptor and serotonin 2A receptor involved in receptor trafficking and signal transduction

[Objective] PACAP (pituitary adenylate cyclase-activating polypeptide) is a multifunctional neuropeptide that regulates a wide array of physiological responses, including, e.g. emotion, cognition and motor function. We previously demonstrated that PACAP-deficient mice display remarkable psychomotor disturbances, most of which were ameliorated with the atypical antipsychotic risperidone and the selective serotonin 2A receptor (5-HT2AR) antagonist ritanserin. These findings suggest a possible alteration of 5-HT2AR signaling in PACAP-deficient mice and a functional interaction between PACAP and 5-HT2AR-mediated 5-HT signaling. However, the underlying mechanisms remain unclear. Recent studies have demonstrated that some GPCRs can form heterodimers, potentially influencing pharmacological signaling pathways and receptor internalization. Here, we therefore investigated the relationship between PACAP-specific receptor (PAC1R) and 5-HT2AR using the NanoBiT protein and protein interaction assay system.