Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

• Published in: The Journal of biological chemistry Vol. 283; no. 45; pp. 30901 - 30910
• Main Authors: Pai, Vaibhav P., Horseman, Nelson D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Electric Impedance; Female; Humans; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mechanisms of Signal Transduction; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Serotonin - metabolism; Serotonin - pharmacology; Tight Junctions - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M802476200

Mammary gland homeostasis and the lactation-to-involution switch are regulated by serotonin (5-hydroxytryptamine (5-HT)). Mammary epithelial tight junctions are physiological targets of 5-HT, and their disruption marks an early stage of mammary gland involution. In these studies, we have identified signal transduction mechanism employed by 5-HT during regulation of mammary gland transepithelial resistance. Transepithelial electrical resistance and tight junction protein architecture were studied in cultures of MCF10A human mammary epithelial cells. Serotonin had biphasic effects on mammary epithelial resistance. At lower concentrations and earlier time points, 5-HT potentiated epithelial transmembrane resistance, whereas at higher concentrations and later time points, 5-HT decreased transepithelial electrical resistance and disrupted tight junctions. Both the early and delayed actions of 5-HT were mediated by the 5-HT7 receptor through activation of Gs/cAMP. 5-HT induced the activities of both protein kinase A and p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase abrogated 5-HT-induced disruption of mammary epithelial tight junctions (the delayed effect). In contrast, inhibition of protein kinase A prevented the increased epithelial resistance in response to 5-HT (the transient effect). These studies imply an integrated set of mechanisms whereby transient, modest activation of 5-HT7 promotes tight junction integrity, and sustained 5-HT7 activation drives involution by disrupting tight junctions.