Novel α1-Adrenergic Receptor Signaling Pathways: Secreted Factors and Interactions with the Extracellular Matrix

• Published in: Molecular pharmacology Vol. 70; no. 1; p. 129
• Main Authors: Ting Shi, Zhong-Hui Duan, Robert Papay, Elzbieta Pluskota, Robert J. Gaivin, Carol A. de la Motte, Edward F. Plow, Dianne M. Perez
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.07.2006
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.105.020735

α 1 -Adrenergic receptor (α 1 -ARs) subtypes (α 1A , α 1B , and α 1D ) regulate multiple signal pathways, such as phospholipase C, protein kinase C (PKC), and mitogen-activated protein kinases. We employed oligonucleotide microarray technology to explore the effects of both short- (1 h) and long-term (18 h) activation of the α 1A -AR to enable RNA changes to occur downstream of earlier well characterized signaling pathways, promoting novel couplings. Polymerase chain reaction (PCR) studies confirmed that PKC was a critical regulator of α 1A -AR-mediated gene expression, and secreted interleukin (IL)-6 also contributed to gene expression alterations. We next focused on two novel signaling pathways that might be mediated through α 1A -AR stimulation because of the clustering of gene expression changes for cell adhesion/motility (syndecan-4 and tenascin-C) and hyaluronan (HA) signaling. We confirmed that α 1 -ARs induced adhesion in three cell types to vitronectin, an interaction that was also integrin-, FGF7-, and PKC-dependent. α 1 -AR activation also inhibited cell migration, which was integrin- and PKC-independent but still required secretion of FGF7. α 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. Long cable structures of HA can bind leukocytes, which this suggests that α 1 -ARs may be involved in proinflammatory responses. Our results indicate α 1 -ARs induce the secretion of factors that interact with the extracellular matrix to regulate cell adhesion, motility and proinflammatory responses through novel signaling pathways.