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 Ca concentrations ([Ca]) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca] were detected by changes in the Fluo-4 AM reagent emission. PYY (3-36) significantly increased [Ca] from the concentration of 10M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3-36)-increase in [Ca] remained unchanged even in Ca-free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca-ATPase pump (SERCA pump) inhibition partially prevent the PYY (3-36)-increase of [Ca] and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3-36)-increase of [Ca]. 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 [Ca], 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 [Ca] increase induced by the peptide, suggesting that PYY (3-36)-induced [Ca] increase in hippocampal neurons occurs via Y2Rs.