Role of adrenergic receptor signalling in neuroimmune communication.

Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically ß-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.

Carvedilol Prevents Redox Inactivation of Cardiomyocyte Β1-Adrenergic Receptors.

The mechanism that leads to a decrease in ß1-adrenergic receptor (ß1AR) expression in the failing heart remains uncertain. This study shows that cardiomyocyte ß1AR expression and isoproterenol responsiveness decrease in response to oxidative stress. Studies of mechanisms show that the redox-dependent decrease in ß1AR expression is uniquely prevented by carvedilol and not other ßAR ligands. Carvedilol also promotes the accumulation of N-terminally truncated ß1ARs that confer protection against doxorubicin-induced apoptosis in association with activation of protein kinase B. The redox-induced molecular controls for cardiomyocyte ß1ARs and pharmacologic properties of carvedilol identified in this study have important clinical and therapeutic implications.

Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease.

The new horizon for cardiac therapy may lie beneath the surface, with the downstream mediators of G protein-coupled receptor (GPCR) activity. Targeted approaches have shown that receptor activation may be biased toward signaling through G proteins or through GPCR kinases (GRKs) and ß-arrestins, with divergent functional outcomes. In addition to these canonical roles, numerous noncanonical activities of GRKs and ß-arrestins have been demonstrated to modulate GPCR signaling at all levels of receptor activation and regulation. Further, research continues to identify novel GRK/effector and ß-arrestin/effector complexes with distinct impacts on cardiac function in the normal heart and the diseased heart. Coupled with the identification of once orphan receptors and endogenous ligands with beneficial cardiovascular effects, this expands the repertoire of GPCR targets. Together, this research highlights the potential for focused therapeutic activation of beneficial pathways, with simultaneous exclusion or inhibition of detrimental signaling, and represents a new wave of therapeutic development.