In conclusion we have shown that mGlu receptors negatively
In conclusion, we have shown that mGlu7 receptors negatively regulate α1-adrenergic receptor signalling in heterologous expression systems, E64d tissue and living animals. This interaction might represent a protective mechanism aimed at restraining an excessive activation of noradrenergic transmission that may amplify responses to stress causing fear and anxiety (Itoi and Sugimoto, 2010, Szabadi, 2013, Montoya et al., 2016) and may also have detrimental consequences on cognitive function (Jett and Morilak, 2013). In addition, the cross-talk between mGlu7 and α1-adrenergic receptors might be targeted by therapeutic intervention in disorders characterized by an increased or reduced activity of central noradrenergic neurons, e.g., opiate withdrawal syndrome and major depression, respectively.
Introduction Chronic stress is the body's response to emotional pressure experienced for a prolonged period of time and it involves the release of stress hormones like cortisol, epinephrine and norepinephrine. Long-term exposure to stress causes high blood levels of these hormones, which increases the risk for numerous diseases. It has been shown that circulating stress hormones slow down wound healing, reactivate latent herpes viruses, and enhance the risk for infectious disease, cardiovascular diseases, type 2 diabetes, mental health problems, and some cancers (Godbout and Glaser, 2006), implicating a central role of the immune system in mediating the health consequences of chronic stress. Indeed, the immune system is directly influenced by the stress hormones glucocorticoids and catecholamines (Elenkov et al., 2000) and communicates bidirectionally with the central nervous and endocrine systems (Glaser and Kiecolt-Glaser, 2005). The field of psychoneuroimmunology investigates key mechanisms of how stress can translate into changes in immune function. Many studies indicate stress-induced immunosuppression with reduced killer cell cytotoxicity, blunted humoral responses to immunization and decreased proliferation of lymphocytes (Segerstrom and Miller, 2004). Furthermore, psychological disorders have been associated with elevated production of pro-inflammatory markers. For instance, inflammatory cytokines might contribute to the development of depression (Felger and Lotrich, 2013). Posttraumatic stress disorder (PTSD) has also been associated with an enhanced production of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α by peripheral blood mononuclear cells (Gola et al., 2013); and recent studies reported a correlation between anxiety symptoms and increased C-reactive protein (CRP) as well as cytokine levels (Liukkonen et al., 2011; Pitsavos et al., 2006). At the cellular level, cortisol, epinephrine and norepinephrine bind to glucocorticoid and adrenergic receptors present in many somatic cells. Cortisol binds to the glucocorticoid receptor in the cytoplasm, and the hormone-receptor complex is then translocated into the nucleus where it activates a battery of genes (Reddy et al., 2009). Epinephrine and norepinephrine bind to the corresponding adrenergic receptors β- and α-AR which are prototypical members of the G-protein-coupled receptors (GPCR) family that are located at the plasma membrane. Activation of β2-AR by epinephrine leads to its conformational change and the generation of the second messenger cyclic adenosine monophosphate (cAMP). The activated β-AR is later phosphorylated, which results in binding of β-arrestin and subsequent receptor desensitisation (Vasudevan et al., 2011). Persistent stress-mediated activation of intracellular signalling due to chronic release of epinephrine and/or norepinephrine has detrimental effects on certain cellular molecules. For instance, there is evidence that catecholamines induce DNA damage in lymphocytes (Crespo and Bicho, 1995; Djelic et al., 2015). Hara and collaborators demonstrated that epinephrine triggers a DNA-damage signalling cascade in various cell lines via activation of β2-adrenergic receptors (β2-AR) and β-arrestin-1 (Hara et al., 2011). Two major pathways have been elucidated to explain β2-AR induced DNA damage: (i) Gs alpha subunit protein kinase A (Gs-PKA) signalling, which induces oxidative stress that directly damages DNA (Yan et al., 2007) and (ii) receptor-dependent recruitment of β-arrestin-1, which leads to nuclear export and degradation of p53 tumour suppressor protein (Hara et al., 2011; Hara et al., 2013), thereby impairing the DNA damage checkpoint and repair cascade. Additionally, it has been shown that DNA strand break formation after epinephrine exposure was significantly reduced by concomitant treatment with quercetin or catalase suggesting that epinephrine may exhibit genotoxic effects in cultured human lymphocytes, most likely due to production of reactive oxygen species (ROS) (Djelic et al., 2015). On the other hand, ROS production is important in G protein-dependent and β-arrestin-dependent signalling (Singh and Moniri, 2014). Inhibition of intracellular ROS prevents β-arrestin and G-protein-mediated phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) after stimulation of β2-AR (Singh and Moniri, 2012).