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Serotonin induces the increase in intracellular Ca 2+ that enhances neurite outgrowth in PC12 cells via activation of 5‐HT 3 receptors and voltage‐gated calcium channels
Author(s) -
Homma Kohei,
Kitamura Yoshiichiro,
Ogawa Hiroto,
Oka Kotaro
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20894
Subject(s) - thapsigargin , neurite , 5 ht receptor , voltage dependent calcium channel , receptor , t type calcium channel , ketanserin , channel blocker , serotonin , chemistry , microbiology and biotechnology , calcium signaling , agonist , calcium , endocrinology , biology , signal transduction , medicine , intracellular , biochemistry , in vitro
Abstract As a neurotransmitter and neuromodulator, serotonin (5‐HT) influences neuronal outgrowth in the nervous systems of several species. In PC12 cells, 5‐HT is known to have neuritogenic effects, although the signal transduction pathway responsible for these effects is not understood. In this study, we hypothesized that a 5‐HT‐induced increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) could be involved in mediating the effects of 5‐HT. Application of 5‐HT to PC12 cells enhanced nerve growth factor (NGF)‐induced neurite outgrowth in a dose‐dependent manner, and the sensitivity of this neuritogenic effect was increased in differentiated PC12 cells. In accordance, an increase in [Ca 2+ ] i was observed following application of 5‐HT in differentiated PC12 cells. This increase was amplified by further NGF treatment. 5‐HT‐induced increases in [Ca 2+ ] i were inhibited by MDL 72222, a selective 5‐HT 3 receptor antagonist, and nifedipine, an L‐type calcium channel blocker, but not by ketanserin, a 5‐HT 2 receptor antagonist, or thapsigargin, a specific inhibitor of endoplasmic reticulum Ca 2+ ‐ATPase. These pharmacological tests indicated that 5‐HT‐induced increases in [Ca 2+ ] i are mediated by activation of voltage‐gated calcium channels via 5‐HT 3 receptors and that 5‐HT‐induced increases in [Ca 2+ ] i are likely to be independent of activation of 5‐HT 2 receptors in PC12 cells. Furthermore, the neuritogenic effect of 5‐HT was suppressed by MDL 72222, nifedipine, calmodulin (CaM) inhibitor, and calcineurin inhibitors. Taken together, our results indicate that 5‐HT‐induced increases in [Ca 2+ ] i , which are mediated via 5‐HT 3 receptors and L‐type calcium channels in PC12 cells, and subsequent activation of CaM and calcineurin enhance NGF‐induced neurite outgrowth. © 2006 Wiley‐Liss, Inc.