Novel α 1 ‐adrenergic receptor signaling pathways: Secreted factors and extracellular matrix regulate cell adhesion, motility and transcription

Abstract

α1-adrenergic receptor (α1-ARs) subtypes (α1A, α1B and α1D) regulate multiple signal pathways such as PLC, PKC, and MAPKs. We employed microarray technology to explore the effects of both short (1h) and long-term (18h) activation of the α1A-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 gene expression with secreted growth factors (IL-6, FGF7) also contributing to expression alterations. We next focused on two novel pathways that may be mediated through α1A-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 α1-ARs mediated vitronectin-dependent cell adhesion in three cell types that was also integrin and FGF7-dependent. α1-AR activation also inhibited cell migration, which was substrate-independent suggesting regulation of cell motility. α1-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 α1-ARs may be involved in pro-inflammatory responses. Our results indicate α1-ARs interact with the extracellular matrix to regulate cell adhesion, motility and pro-inflammatory responses through novel signaling pathways.