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 10−11M 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. •PYY (3–36) induce a sustained increase in [Ca2+]i in hippocampal neurons.•PYY (3–36) mobilizes calcium from the neuronal ER stores towards the cytoplasm.•IP3R is involved in the increase of [Ca2+]i elicited by PYY (3–36).•PYY (3–36) could lead to a modulation of K+ channels.•PYY (3–36) increases [Ca2+]i via Y2 receptors;