Peptide YY (3-36) modulates intracellular calcium through activation of the phosphatidylinositol pathway in hippocampal neurons

Peptide YY (PYY) belongs to the neuropeptide Y (NPY) family, which also includes the pancreatic polypeptide (PP) and NPY. PYY is secreted by the intestinal L cells, being present in the blood stream in two active forms capable of crossing the blood brain barrier, PYY (1-36) and its cleavage product, PYY (3-36). PYY is a selective agonist for the Y2 receptor (Y2R) and these receptors are abundant in the hippocampus. Here we investigated the mechanisms by which PYY (3-36) regulates intracellular Ca2 + concentrations ([Ca2 +]i) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca2 +]i were detected by changes in the Fluo-4 AM reagent emission. PYY (3-36) significantly increased [Ca2 +] from the concentration of 10− 11 M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3-36)-increase in [Ca2 +]i remained unchanged even in Ca2 +-free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase pump (SERCA pump) inhibition partially prevent the PYY (3-36)-increase of [Ca2 +]i and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3-36)-increase of [Ca2 +]i. Taken together, our data strongly suggest that PYY (3-36) mobilizes calcium from the neuronal endoplasmic reticulum (ER) stores towards the cytoplasm. Next, we showed that PYY (3-36) inhibited high K+-induced increases of [Ca2 +]i, suggesting that PYY (3-36) could also act by activating G-protein coupled inwardly rectifying potassium K+ channels. Finally, the co-infusion of the Y2 receptor (Y2R) antagonist BIIE0246 with PYY (3-36) abolished the [Ca2 +]i increase induced by the peptide, suggesting that PYY (3-36)-induced [Ca2 +]i increase in hippocampal neurons occurs via Y2Rs.