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The Journal of Neuroscience, March 15, 2003, 23(6):2049

Calcium Receptor-Induced Serotonin Secretion by Parafollicular Cells: Role of Phosphatidylinositol 3-Kinase-Dependent Signal Transduction Pathways

Kuo-peing Liu¹, Andrew F. Russo², Shu-chi Hsiung¹, Mella Adlersberg¹, Thomas F. Franke³, Michael D. Gershon⁴, and Hadassah Tamir^{1, 4}

¹ Division of Neuroscience, New York State Psychiatric Institute, New York, New York 10032, ² Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa, 52242, and Departments of ³ Pharmacology and ⁴ Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032

Elevation of extracellular Ca²⁺ ([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 Gq with subsequent activation of protein kinase C- (PKC). 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/p110 (PI3-K) immunocomplexes was elevated by [Ca²⁺]_e and activated by G subunits. In addition, secretion of 5-HT was antagonized by the expression of a minigene encoding a peptide scavenger of G subunits (C-terminal fragment peptide of bovine -adrenergic receptor kinase). One target of PI3-K activity is phosphoinositide-dependent kinase-1 (PDK1), which in turn activated PKC. Expression of a dominant-negative PKC in PF cells reduced 5-HT secretion. Together, these observations establish that [Ca²⁺]_e evokes 5-HT secretion from PF cells by stimulating both Gq- and G-signaling pathways downstream of the CaR. The cascade subsequently activates PI3-K-dependent signaling that is coupled to PDK1 and the downstream effector PKC, and results in an increase in 5-HT release.

Key words: serotonin; parafollicular cells; gene transfer; atypical PKC; G subunits; secretion; calcitonin

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2362049-09$05.00/0

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