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  • br Concluding remarks In this small material of


    Concluding remarks In this small material of thirteen pituitary tumors of various kinds, we could not run statistical analysis. However, with a follow-up period of up to five years, we show that
    Disclosure Statement
    Introduction Galanin is a 29/30-residue neuropeptide found in many species, including rats and humans (Tatemoto et al., 1983). Galanin's biological activity is mediated through three different G-protein coupled receptors, galanin receptor subtypes 1–3 (GalR1–GalR3). GalR1 was first cloned from human Bowes melanoma Urolithin A synthesis (Habert-Ortoli et al., 1994), GalR2 from rat hypothalamus (Ahmad et al., 1998, Howard et al., 1997, Smith et al., 1997) and GalR3 was isolated from rat hypothalamic cDNA libraries (Wang et al., 1997). All three receptor subtypes have somewhat different signaling pathways. GalR1 and GalR3 are coupled to Gαi/o and they inhibit adenylyl cyclase release. GalR2 acts via Gq/11 types of proteins and activates phospholipase C and protein kinase or via Gi/o to inhibit neurotransmission (Lang et al., 2007, Runesson et al., 2009a, Ögren et al., 2007). Such signaling through galanin subtypes suggests that different receptors can be involved in different disorders. Galanin has been implicated in several functions in the central nervous system, including the regulation of food consumption, mediated by receptors in the hypothalamic regions, notably the paraventricular (PVN), dorsomedial, lateral, arcuate, and ventromedial nucleus of the hypothalamus. The most striking effect of galanin on feeding is an immediate and robust stimulation of food intake following galanin administered into the ventricle or PVN (Crawley, 1999, Kyrkouli et al., 1986, Kyrkouli et al., 1990, Leibowitz, 2005). All three receptor types can be found in the hypothalamic region (Waters and Krause, 2000), and therefore may mediate this effect. However, the direct pharmacological investigation of the role of specific GalR subtypes in acute feeding stimulation has awaited the development of receptor selective agonists. The present study has two aims. First, we characterized new subtype specific agonist ligands for GalR2 by modifying C-terminal and N-terminal part of Gal(1–13). Galanin itself binds to all three receptor subtypes, but it is known that GalR1 does not tolerate deletions of the N-terminal part of the galanin peptide. This fact has been used previously to design ligands that have better affinity towards GalR2 when compared to GalR1 (Liu et al., 2001, Sollenberg et al., 2006). It is also known that extension of C-terminal and also the N-terminal part of galanin analogues modifies the binding affinity towards galanin receptors (Pooga et al., 1998, Runesson et al., 2009b). Next, we compare these novel subtype selective agonists to GalR1 selective agonist M617 for their ability to stimulate acute consumption of several foods shown to be reliably stimulated by intracerebroventricularly (i.c.v.) administered galanin (Crawley, 1999).
    Materials and methods
    Discussion The present study introduces two novel (M1152 and M1153) and two previously published galanin receptor subtype specific agonist ligands (M1145 and M1151). Novel peptides are based on modifications of the C-terminal and N-terminal parts of Gal(1–13). Design of the C-terminal part of the peptides was based on an article by Pooga and colleagues where different compounds were added orthogonally to the side chain of Lys residue situated at position 14 (Pooga et al., 1998). In our hands, the peptide M1151, corresponding to peptide 40 (Pooga et al., 1998), had a preferential binding towards GalR2, with a Ki of 28.9nM (Table 2). Pooga and colleagues reported that the binding affinity for peptide 40 was 7.8nM at galanin receptors isolated from rat hypothalamic tissues (Pooga et al., 1998). This difference could be caused by number of different factors, for example variation in the used receptor species (Bloomquist et al., 1998, Borowsky et al., 1998). Expression of all three galanin receptors has Urolithin A synthesis been identified in rat hypothalamus, i.e. 14.39pg/μg of GalR1, 10.60pg/μg of GalR2 and 3.37pg/μg of GalR3 RNA (Waters and Krause, 2000). Presumably there is a variation in the receptor species used.