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  • Index Kit 2 receptor PKA signalling in the nucleus was thoug


    PKA signalling in the nucleus was thought to be due to the translocation of the catalytic subunit upon activation from the Index Kit 2 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.
    The endothelin system and endothelin receptors The endothelin system has a multitude of functions in vertebrates. Discovered in the late 1980s, it was first described to control blood pressure levels by vasoconstriction and vasodilation (Arai et al., 1990, Inoue et al., 1989, Masaki, 2004, Sakurai et al., 1990, Yanagisawa et al., 1988). Further on, it was found that the endothelin system functions also in many other aspects of vertebrate physiology and development, such as neurotransmission, wound healing, kidney homeostasis, osmoregulation (in fish), neural crest cell development, and many more (Barton and Yanagisawa, 2008, Hyndman and Evans, 2007, Khimji and Rockey, 2010, Rubanyi and Polokoff, 1994). Misregulation of the endothelin system leads to a multitude of pathological conditions such as cardiovascular, renal, pulmonary, and central nervous system diseases, atherosclerosis, ovarian cancer, and – due to its role in neural crest development – to problems with the development of the enteric nervous system, pigment cells, and the craniofacial skeleton (Bagnato and Rosano, 2008, Kedzierski and Yanagisawa, 2001, Khimji and Rockey, 2010, Pla and Larue, 2003, Schneider et al., 2007, von Websky et al., 2009). At its core, the endothelin system consists of endothelin ligands, 21 amino acid long peptides processed from larger precursor prepro-endothelin proteins, that bind to G-protein coupled receptors (GPCRs) called endothelin receptors (Ednrs) (Fig. 1) belonging to β-group of rhodopsin receptors (Fredriksson et al., 2003). Vertebrate endothelin receptors contain seven transmembrane domains and are usually encoded by seven coding exons. A structurally annotated alignment of representative Ednr protein sequences is presented in Supplementary Fig. S1.