| First Author | Hayata-Takano A | Year | 2021 |
| Journal | Front Endocrinol (Lausanne) | Volume | 12 |
| Pages | 732456 | PubMed ID | 34759890 |
| Mgi Jnum | J:335069 | Mgi Id | MGI:6810340 |
| Doi | 10.3389/fendo.2021.732456 | Citation | Hayata-Takano A, et al. (2021) PACAP-PAC1 Signaling Regulates Serotonin 2A Receptor Internalization. Front Endocrinol (Lausanne) 12:732456 |
| abstractText | Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) display psychomotor abnormalities, most of which are ameliorated by atypical antipsychotics with serotonin (5-HT) 2A receptor (5-HT2A) antagonism. Heterozygous Pacap mutant mice show a significantly higher hallucinogenic response than wild-type mice to a 5-HT2A agonist. Endogenous PACAP may, therefore, affect 5-HT2A signaling; however, the underlying neurobiological mechanism for this remains unclear. Here, we examined whether PACAP modulates 5-HT2A signaling by addressing cellular protein localization. PACAP induced an increase in internalization of 5-HT2A but not 5-HT1A, 5-HT2C, dopamine D2 receptors or metabotropic glutamate receptor 2 in HEK293T cells. This PACAP action was inhibited by protein kinase C inhibitors, beta-arrestin2 silencing, the PACAP receptor PAC1 antagonist PACAP6-38, and PAC1 silencing. In addition, the levels of endogenous 5-HT2A were decreased on the cell surface of primary cultured cortical neurons after PACAP stimulation and were increased in frontal cortex cell membranes of Pacap(-/-) mice. Finally, intracerebroventricular PACAP administration suppressed 5-HT2A agonist-induced head twitch responses in mice. These results suggest that PACAP-PAC1 signaling increases 5-HT2A internalization resulting in attenuation of 5-HT2A-mediated signaling, although further study is necessary to determine the relationship between behavioral abnormalities in Pacap(-/-) mice and PACAP-induced 5-HT2A internalization. |
