PKA signalling in the http www

PKA signalling in the nucleus was thought to be due to the translocation of the catalytic subunit upon activation from the MCB-613 receptor to the nucleus via diffusion [72]. However, a new understanding has emerged, as both the regulatory and catalytic subunits have been identified in the nucleus and functionally separate from the cell surface [[73], [74], [75]]. Functional differences between the two pools of PKA have been identified in cardiomyocytes, with cytoplasmic PKA exerting inotropic effects and the nuclear pool regulating hypertrophic responses [47]. The compartment specific activation of PKA by different subtypes of the α1-AR adds another dimension to their differential physiological and pathological roles. Subtype selective agonists or antagonists could be used to assess these differences in cardiomyocytes.
Conclusion In conclusion, we have provided evidence that the α1-AR family activates the cAMP/PKA pathway in a Gαs-dependent manner. Within this subfamily, there is subtype specific activation of PKA in various cellular compartments. Furthermore, the inability of the ETAR to activate PKA highlights that when studying global effects in cardiac hypertrophy, agonists for GPCRs that canonically couple to Gαq need to be assessed independently for additional signalling phenotypes.
Note added in proof The following is the supplementary data related to this article.
Acknowledgements This work was supported by a grant from the Heart and Stroke Foundation of Canada to TEH and JCT. RDM was supported by a scholarship from the Canadian Institutes of Health Research (CIHR). JCT was supported by a fellowship from Fonds de recherche du Québec Santé (FRQS). RDM and NA were supported by a fellowship and studentship, respectively, from the McGill-CIHR Drug Development Training Program and from the Mathematics of Information Technology and Complex Systems (MITACS). KB was supported by a Faculty of Medicine Doctoral Scholarship and YS received a summer bursary from the Groupe d'étude des protéines membranaires (GEPROM). The authors thank Viviane Pagé for administrative and technical support.
Introduction Ozone is a reactive secondary pollutant which oxidizes biomolecules in the respiratory tract upon inhalation (Bromberg, 2016). The accepted paradigm of ozone-induced lung injury and inflammation involves its direct interaction with lung lining components and generation of oxidized lipid and protein byproducts (Auerbach and Hernandez, 2012), which are responsible for activation of the inflammatory signaling cascade and mediating downstream effects such as lung function decrement, increased vascular permeability, and neutrophilic inflammation. These ozone-induced effects are reversible even if daily exposure continues over several days suggesting tolerance or adaptation (Miller et al., 2016a). The oxidatively-modified reactive byproducts generated locally within the lung are believed to promote local cellular effects, such as stimulating the release of cytokines and chemokines to promote recruitment of neutrophils via activation of NRF2 and NFκB pathways in the lung (Hollingsworth et al., 2007). These reactive byproducts are also thought to promote systemic effects through their release from the lung to circulation. The identity of circulating bioactive molecules and how they contribute to lung effects of air pollutants remains an area of interest. Acute ozone exposure has also been shown to induce pulmonary sensory irritation and C-fiber activation. Upstream events that are involved in this response include neuron firing of the nucleus tractus solitarius (NTS) (Gackière et al., 2011), increases in circulating adrenocorticotropic hormone (ACTH) (Thomson et al., 2013), and cardiac changes through autonomic reflex mechanisms (Arjomandi et al., 2015, Gordon et al., 2014). These events suggest that ozone inhalation is capable of triggering a centrally-mediated neuroendocrine stress response which results in increased release of stress hormones into the systemic circulation (Kodavanti, 2016, Snow et al., 2017). Indeed, we have recently shown that circulating stress hormones such as epinephrine and cortisol/corticosterone rise rapidly after acute ozone exposure in both rodents (Bass et al., 2013, Miller et al., 2015, Miller et al., 2016b) and humans (Miller et al., 2016c). Subsequent ozone-induced lung global gene expression changes mimic those induced by downstream events promoted by β2 adrenergic and glucocorticoid receptor activation, further suggesting that circulating stress hormones might play a key role as mediators of pulmonary responses (Henriquez et al., 2017). The role of circulating adrenal gland-derived stress hormones in ozone-induced lung injury and inflammation in rats was further confirmed by the evidence that bilateral adrenalectomy diminished these ozone effects (Miller et al., 2016b) and associated global lung transcriptional changes (Henriquez et al., 2017).