HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 45, 30901-30910, November 7, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/45/30901    most recent M802476200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pai, V. P. Articles by Horseman, N. D. Search for Related Content PubMed PubMed Citation Articles by Pai, V. P. Articles by Horseman, N. D. Social Bookmarking                      What's this?

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

From the Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267-0576

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 G_s/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.

Received for publication, March 31, 2008 , and in revised form, September 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK52134. This work was also supported by Department of the Army Grant BC052576 (to N. D. H.). This project was also supported by National Research Initiative Competitive Grant 2007-35206-17898 from the United States Department of Agriculture Cooperative State Research, Education, and Extension Service. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular and Cellular Physiology, 231 Albert Sabin way, MSB, Cincinnati, OH 45267-0576. Tel.: 513-558-3019; Fax: 513-558-5738; E-mail: nelson.horseman{at}uc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?