Adrenergic Receptor Signaling Pathway Research Articles

Therapeutic Targets for Heart Failure: Beyond Beta-Adrenergic and Renin-Angiotensin System Blockade

Heart failure is a major healthcare problem and leading cause of death in Western countries. Growing evidence has shown recent improvements in pharmacological therapy, such as receptor-regulating agents, in treating heart failure; however, the morbidity and mortality of heart failure is still high. More recent studies have suggested the presence of additional molecular targets for treating heart failure. Several key molecules in the beta adrenergic receptor signaling pathway play an important role in the progression of heart failure, and transgenic mice studies supported beneficial effects of controlling such molecules in heart failure. In addition, molecules in the renin-angiotensin system or calcium signaling pathway may also be potential targets for treating heart failure. In this review, we focused on putative mechanisms underlying the beneficial effects of regulating these molecules on the progression of heart failure including relevant patents on this topic.

Phosphorylation of Phospholemman (FXYD1) by Protein Kinases A and C Modulates Distinct Na,K-ATPase Isozymes

Phospholemman (FXYD1), mainly expressed in heart and skeletal muscle, is a member of the FXYD protein family, which has been shown to decrease the apparent K(+) and Na(+) affinity of Na,K-ATPase ( Crambert, G., Fuzesi, M., Garty, H., Karlish, S., and Geering, K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 11476-11481 ). In this study, we use the Xenopus oocyte expression system to study the role of phospholemman phosphorylation by protein kinases A and C in the modulation of different Na,K-ATPase isozymes present in the heart. Phosphorylation of phospholemman by protein kinase A has no effect on the maximal transport activity or on the apparent K(+) affinity of Na,K-ATPase alpha1/beta1 and alpha2/beta1 isozymes but increases their apparent Na(+) affinity, dependent on phospholemman phosphorylation at Ser(68). Phosphorylation of phospholemman by protein kinase C affects neither the maximal transport activity of alpha1/beta1 isozymes nor the K(+) affinity of alpha1/beta1 and alpha2/beta1 isozymes. However, protein kinase C phosphorylation of phospholemman increases the maximal Na,K-pump current of alpha2/beta1 isozymes by an increase in their turnover number. Thus, our results indicate that protein kinase A phosphorylation of phospholemman has similar functional effects on Na,K-ATPase alpha1/beta and alpha2/beta isozymes and increases their apparent Na(+) affinity, whereas protein kinase C phosphorylation of phospholemman modulates the transport activity of Na,K-ATPase alpha2/beta but not of alpha1/beta isozymes. The complex and distinct regulation of Na,K-ATPase isozymes by phosphorylation of phospholemman may be important for the efficient control of heart contractility and excitability.

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

alpha1-Adrenergic receptor (alpha1-ARs) subtypes (alpha1A, alpha1B, and alpha1D) 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 alpha1A-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 alpha1A-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 alpha1A-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 alpha1-ARs induced adhesion in three cell types to vitronectin, an interaction that was also integrin-, FGF7-, and PKC-dependent. alpha1-AR activation also inhibited cell migration, which was integrin- and PKC-independent but still required secretion of FGF7. alpha1-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 alpha1-ARs may be involved in proinflammatory responses. Our results indicate alpha1-ARs induce the secretion of factors that interact with the extracellular matrix to regulate cell adhesion, motility and proinflammatory responses through novel signaling pathways.

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

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.