In addition to our results Chen et al showed

In addition to our results, Chen et al. showed that administration of the GalR1 antagonist M40 improves cardiac function and attenuates cardiac remodeling in rats with heart failure [26]. These effects might be attributed to M40 suppression of galanin inhibitory effect on the vagal nerve in heart failure resulting in attenuation of the imbalance of the autonomic nervous system. The positive inotropic effect of galanin, associated with an improvement in contractility of isolated guinea pig papillary muscle, was found during hypoxia [27]. Myocardial infarction stimulated the formation of mRNA of galanin and galanin protein in sympathetic neurons in rats [28]. Notably, the expression of galanin increased only in the region of the LV distal to coronary artery ligation thus indicating the possibility of its transport on the regenerating nerve endings. In diabetic rats, galanin exerted the ability to maintain myocardial GLUT4 levels and hence glucose uptake by cardiomyocytes [29]. This effect of galanin on GLUT4 appears to be mediated through the GalR1 receptor, since intracerebral infusion of M617, the GalR1 agonist, caused a significant increase in cardiac GLUT4 [30]. Taken together, these data demonstrate that galaninergic system represents an important mediator of cardiometabolic remodeling in pathophysiological conditions.
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Conflict of interest
Acknowledgements This work was supported by the Russian Foundation for Basic Research (grant Nos. 18-015-00009 and 18-015-00008). The authors are grateful to Dr. Oksana Kunduzova (National Institute of Health and Medical Research, Toulouse, France) for the purchase of rat galanin (1–29)-NH2.
Introduction Mood disorders, including depression and anxiety, are among the most prevalent mental illnesses with high socioeconomic impact (Gelenberg, 2010, Wittchen et al., 2011). Although the underlying mechanisms have not yet been clearly defined in the last decade the importance of the role of neuropeptides, including Galanin (GAL), and/or their receptors in the treatment of stress-related mood disorders is becoming increasingly apparent (Kormos and Gaszner, 2013). GAL is a 29 amino gap junctions neuropeptide (Tatemoto et al., 1983) widely distributed in neurons within the central nervous system (CNS) including raphe nuclei, cerebral cortex and hippocampus (Jacobowitz et al., 2004) among other nuclei involved in mood disorders. Three GAL receptor subtypes (GAL1–3 receptors) have been described (Branchek et al., 2000, Mitsukawa et al., 2008). GAL1 and GAL2 receptors, in particular, are found in many regions of the CNS as demonstrated with in situ hybridization, radioligand binding, and immunohistochemical studies (Jacobowitz et al., 2004) and have all high affinity for GAL. GAL1 and GAL3 receptors mainly activate inhibitory G proteins Gi/Go, while GAL2 receptor primarily couples to Gq/G11 to mediate excitatory signaling (Branchek et al., 2000). The three GAL receptors participate in a number of functions in the CNS including neuroendocrine levels, mood regulation, pain control, cardiovascular functions, addiction and food intake (Lu et al., 2007, Kuteeva et al., 2008, Mitsukawa et al., 2008, Diaz-Cabiale et al., 2010, Juhasz et al., 2014, Lang et al., 2015). Not only GAL but also the GAL fragments like GAL N-terminal fragment 1–15 [GAL(1–15)] are active in the CNS (Hedlund and Fuxe, 1996, Diaz-Cabiale et al., 2005, Diaz-Cabiale et al., 2010, Millon et al., 2015, Millon et al., 2016). Structure-activity studies described that in the brain, N-terminal fragments of GAL are biologically active, whereas C-terminal fragments are inactive (Diaz-Cabiale et al., 1998) and they act as agonists in several physiological functions (Diaz-Cabiale et al., 1998, Diaz-Cabiale et al., 2005), suggesting a receptor-mediated action. Although the three GAL receptors subtypes show higher affinity for GAL than for GAL(1–15) (Branchek et al., 1998), the presence of specific binding sites for this GAL fragment in the CNS also in areas lacking [125I]- GAL binding sites indicated a powerful role of GAL fragments, especially in the dorsal hippocampus, neocortex and striatum (Hedlund et al., 1992). Only GAL(1–15), but not GAL, can antagonically modulate the serotonin 5-HT1A receptors in the dorsal hippocampus, and this effect was blocked by the GAL receptor antagonist M35 (Hedlund et al., 1994). In the ventral limbic cortex, N-terminal GAL fragments can more stringy and more potently reduce postjunctional 5-HT1A receptor recognition than GAL, where high-affinity GAL receptors also exist (Diaz-Cabiale et al., 2000, Diaz-Cabiale et al., 2010). The formation of GAL1/GAL2 heteroreceptors highly specific for GAL fragments will explain the different effects between GAL and GAL(1–15) (Fuxe et al., 2008, Fuxe et al., 2012, Millon et al., 2015).