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First published on April 14, 2006; DOI: 10.1124/mol.105.020735

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Received for publication November 11, 2005.
Revised March 27, 2006.
Accepted for publication April 14, 2006.

Novel {alpha}1-Adrenergic Receptor Signaling Pathways: Secreted Factors and Interactions with the Extracellular Matrix

Ting Shi 1, Zhong-Hui Duan 2, Robert Papay 1, Elzbieta Pluskota 1, Robert J. Gaivin 1, Carol A. de la Motte 1, Edward F Plow 1, Dianne M. Perez 1*

1 The Cleveland Clinic Foundation 2 University of Akron

* Address correspondence to: E-mail: perezd{at}ccf.org

Abstract

{alpha}1-adrenergic receptor ({alpha}1-ARs) subtypes ({alpha}1A, {alpha}1B and {alpha}1D) regulate multiple signal pathways such as PLC, PKC, and MAPKs. We employed oligonucleotide microarray technology to explore the effects of both short (1h) and long-term (18h) activation of the {alpha}1A-AR to enable RNA changes to occur downstream of earlier well-characterized signaling pathways, promoting novel couplings. PCR studies confirmed that PKC was a critical regulator of {alpha}1A-AR mediated gene expression with secreted IL-6 also contributing to gene expression alterations. We next focused on two novel pathways that may be mediated through {alpha}1A-AR stimulation, due to the clustering of gene expression changes for cell adhesion/motility (syndecan-4 and tenascin-C) and hyaluronan (HA) signaling. We confirmed that {alpha}1-ARs induced adhesion in three cell types to vitronectin, an interaction that was also integrin, FGF7, and PKC-dependent. {alpha}1-AR activation also inhibited cell migration, which was integrin and PKC-independent but still required secretion of FGF7. {alpha}1-AR activation also increased the expression and deposition of HA, a glycosaminoglycan, which displayed two distinct structures: pericellular coats and long cable structures, as well as increasing expression of the HA receptor, CD44. Since long cable structures of HA can bind leukocytes, this suggests that {alpha}1-ARs may be involved in pro- inflammatory responses. Our results indicate {alpha}1-ARs signal to induce the secretion of factors that interact with the extracellular matrix to regulate cell adhesion, motility and pro-inflammatory responses through novel signaling pathways.


Key words: Adrenergic, Protein Kinase C, Signaling network analyses, Regulation of gene expression


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