RRC ID 71918
Author Hayata-Takano A, Shintani Y, Moriguchi K, Encho N, Kitagawa K, Nakazawa T, Hashimoto H.
Title PACAP-PAC1 Signaling Regulates Serotonin 2A Receptor Internalization.
Journal Front Endocrinol (Lausanne)
Abstract 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, β-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.
Volume 12
Pages 732456
Published 2021-1-1
DOI 10.3389/fendo.2021.732456
PMID 34759890
PMC PMC8574227
MeSH Animals Cells, Cultured HEK293 Cells Humans Mice Mice, Inbred ICR Mice, Knockout Neurons / metabolism Pituitary Adenylate Cyclase-Activating Polypeptide / genetics Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism Pituitary Adenylate Cyclase-Activating Polypeptide / physiology* Protein Transport / genetics Receptor, Serotonin, 5-HT2A / metabolism* Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / physiology* Signal Transduction / physiology
IF 3.644
Human and Animal Cells 293T(RCB2202)