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Calcium receptor-induced serotonin secretion by parafollicular cells: role of phosphatidylinositol 3-kinase-dependent signal transduction pathways
Journal article   Open access   Peer reviewed

Calcium receptor-induced serotonin secretion by parafollicular cells: role of phosphatidylinositol 3-kinase-dependent signal transduction pathways

Kuo-peing Liu, Andrew F Russo, Shu-chi Hsiung, Mella Adlersberg, Thomas F Franke, Michael D Gershon and Hadassah Tamir
The Journal of neuroscience, Vol.23(6), pp.2049-2057
03/15/2003
DOI: 10.1523/JNEUROSCI.23-06-02049.2003
PMCID: PMC6742020
PMID: 12657663
url
https://doi.org/10.1523/JNEUROSCI.23-06-02049.2003View
Published (Version of record) Open Access

Abstract

Elevation of extracellular Ca2+ (increase[Ca2+]e) stimulates the Ca2+ receptor (CaR) to induce secretion of 5-hydroxytryptamine (5-HT) from the calcium-sensing parafollicular (PF) cells. The CaR has been reported to couple to Galpha(q) with subsequent activation of protein kinase C-gamma (PKCgamma). We have identified a parallel transduction pathway in primary cultures of sheep PF cells by using a combinatorial approach in which we expressed adenoviral-encoded dominant-negative signaling proteins and performed in vitro kinase assays. The role of the CaR was established by expression of a dominant-negative CaR that eliminated calcium-induced 5-HT secretion but not secretion in response to KCl or phorbol esters. The calcium-induced secretion was inhibited by a dominant-negative p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K). PI3-K activity was also assayed using isoform-specific antibodies. The activity of p85/p110beta (PI3-Kbeta) immunocomplexes was elevated by increase[Ca2+]e and activated by Gbetagamma subunits. In addition, secretion of 5-HT was antagonized by the expression of a minigene encoding a peptide scavenger of Gbetagamma subunits (C-terminal fragment peptide of bovine beta-adrenergic receptor kinase). One target of PI3-K activity is phosphoinositide-dependent kinase-1 (PDK1), which in turn activated PKCzeta. Expression of a dominant-negative PKCzeta in PF cells reduced 5-HT secretion. Together, these observations establish that increase[Ca2+]e evokes 5-HT secretion from PF cells by stimulating both Galpha(q)- and Gbetagamma-signaling pathways downstream of the CaR. The betagamma cascade subsequently activates PI3-Kbeta-dependent signaling that is coupled to PDK1 and the downstream effector PKCzeta, and results in an increase in 5-HT release.
 Phosphorylation Transfection Gene Expression Protein Kinase C - genetics Calcium - metabolism Heterotrimeric GTP-Binding Proteins - metabolism Phosphatidylinositol 3-Kinases - metabolism Protein Subunits - metabolism Extracellular Space - metabolism Cyclic AMP-Dependent Protein Kinases - genetics Genes, Dominant Isoenzymes - metabolism Protein Kinase C - metabolism Thyroid Gland - cytology Peptide Fragments - genetics 3-Phosphoinositide-Dependent Protein Kinases Protein-Serine-Threonine Kinases - metabolism Thyroid Gland - drug effects Protein Subunits - genetics Calcium-Binding Proteins - metabolism Cyclic AMP-Dependent Protein Kinases - biosynthesis Proto-Oncogene Proteins - metabolism Calcium - pharmacology Cell Separation Isoenzymes - genetics Cells, Cultured Thyroid Gland - secretion Peptide Fragments - biosynthesis Phosphatidylinositol 3-Kinases - genetics Proto-Oncogene Proteins c-akt Animals Signal Transduction - drug effects GTP-Binding Protein alpha Subunits, Gq-G11 Serotonin - metabolism Serotonin - secretion Sheep Signal Transduction - physiology Thyroid Gland - metabolism Calcium-Binding Proteins - genetics beta-Adrenergic Receptor Kinases

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