Galanin was isolated from the porcine gastrointestinal tract by Dr. Tatemoto in the laboratory of Professor Mutt in 1983. It was given its name by its glycine C-terminus and alanine N-terminus. It is a highly conserved peptide consisting of 29 amino acids in most species and C-terminally amidated. However, the human form of galanin consists of a 30-amino acid residue that is not C-terminally amidated. Whereas the C-terminal amino acid of galanin in the pig is alanine, it is threonine in rat galanin and serine in human galanin. Nevertheless, the name galanin has been retained for the peptide in rats and humans. The human galanin gene is located on chromosome 11q13.3-q13.5 and consists of six exons. The first exon is noncoding, whereas the coding region for progala-nin consists of five exons (Fig. 5). Progalanin is a 123-residue peptide, which includes the signal peptide (23 amino acids), galanin (30 amino acids), and galanin message-associated peptide (GMAP, 61 amino acids). Posttranslational modifications yield the 91-amino acid progalanin consisting of galanin and GMAP. The N-terminal amino acids 1-13 in the galanin molecule are encoded in exon 3 and the remaining 17 amino acids in exon 4, which is of interest because it is the N-terminal end that is biologically active.

30 91


Figure 5 Schematic representation of the galanin gene and progalanin. The first exon is non-encoding, exon 2 encodes the signal peptide, exons 3-5 encode for the sequence corresponding to galanin, and exons 5 and 6 encode for the sequence corresponding to GMAP (galanin message-associated peptide). At the bottom of the figure are the amino acid sequences of human (h), porcine (p), and rat (r) galanin. * indicates a C-terminal NH2 group.

Galanin is widely distributed in the peripheral nervous system, in both the sympathetic and para-sympathetic nerves. It exerts a wide spectrum of actions, such as stimulatory or inhibitory influences on smooth muscle cells depending on location and inhibition of secretion of gastrointestinal hormones and gastric acid. Galanin is also widely distributed in the central nervous system with major localization to the nuclei of the septum-basal forebrain complex, the hypothalamus, and the dorsal raphe nucleus. Centrally, a main function of galanin is its stimulation of feeding, as has been demonstrated in rats. In the pancreas, a dense galanin innervation of the islets was first demonstrated in dogs. These nerves were found to be sympathetic, because galanin is colocalized with tyrosine hydroxylase in nerve terminals and because galanin occurs in nerve cell bodies in the celiac ganglion. In other species, islets are innervated by galanin nerves, although with a lesser density than in the dog. Galanin has been demonstrated to potently inhibit insulin secretion and to stimulate glucagon secretion in a number of experimental systems both in vivo and in vitro. The potential effect of GMAP on insulin secretion has also been examined in one study in isolated islets. However, the peptide had no influence over a wide dose range and at different glucose concentrations.

Three galanin receptors have been cloned and called GalR1, GalR2, and GalR3, respectively. They are all encoded by different genes located on different chromosomes (GalR1 on 18q23, GalR2 on 17q25.3, and

GalR3 on 22q13.1), and they are all G-protein-coupled receptors. The structural organization of the genes encoding for GalR2 and GalR3 are conserved during evolution, suggesting a common evolutionary origin, whereas the structure of the GalR1 gene is unique among the G-protein-coupled receptors, the relevance of which is not yet known. It is this galanin receptor subtype, GalRl, that has been shown to be expressed in insulin producing cells. Whereas the structure of the GalR1 gene is different between species, the structure of the receptor itself shows high conservation during evolution, and human (349 amino acids) and mouse (348 amino acids) GalRl displays 93% identity. The powerful inhibitory influence of galanin in rodent islets has been shown to be accompanied by a complex signaling mechanism involving hyperpolarization due to the opening of K+ channels and a concomitant reduction in the cytosolic concentration of Ca2 + , although reduced formation of cAMP and inhibition of the exocytotic mechanism by a direct effect on the exocytosis machinery may also contribute.

Functional studies have indicated that galanin contributes to the sympathetically induced inhibition of insulin secretion. Thus, it has been demonstrated that galanin is released from the dog pancreas during sympathetic nerve activation and that the amount of galanin released under these conditions is sufficient to mimic the inhibition of insulin secretion induced by sympathetic nerve stimulation. The physiology of galanin has also been studied in a physiological model of swimming mice, in which swimming for 2 min is accompanied by a 50% inhibition of glucose-stimulated insulin secretion as a sign of the stress associated with the physical exercise. When galanin was immu-noneutralized in these mice by pretreatment with a high-titer galanin antiserum, the impairment of glucose-stimulated insulin secretion during the swimming was abolished. This suggests that galanin released from the sympathetic nerves during the swimming contributes to the inhibition of insulin secretion. Studies to conclusively establish this remain to be performed, however. One approach might be the use of selective GalRl antagonists, a few of which have been reported, like galantide. Another approach would be the use of galanin- or GalRl-deficient mice. It must be emphasized, however, that species differences seem to be of particular relevance regarding the role of galanin in islet function. For example, whereas it is established that extensive galanin innervation exists in dog islets, there is only scanty innervation in rat or human islets. Furthermore, whereas potent inhibition by galanin of insulin secretion has been reported in dogs, no such effect is evident in humans. In addition, in the pig galanin has been shown to stimulate, not inhibit, insulin secretion. Therefore, the involvement of galanin in islet physiology remains to be established.

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