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Colorectal cancer (CRC) is the second most common cause of cancer in women and the third in men. The postoperative pathomorphological evaluation of patients with CRC is extremely important for future therapeutic decisions. Although our previous studies demonstrated high galanin (GAL) presence within tumor tissue and an elevated concentration of GAL in the serum of CRC patients, to date, there is a lack of data regarding GAL receptor (GalR) protein expression in CRC cells. Therefore, the aim of this study was to evaluate the presence of all three types of GalRs (GalR1, GalR2 and GalR3) within epithelial cells of the human colon and CRC tissue with the use of the immunohistochemical method and to correlate the results with the clinical-pathological data. We found stronger immunoreactivity of GalR1 and GalR3 in CRC cells compared to epithelial cells of the unchanged mucosa of the large intestine. No differences in the GalR2 protein immunoreactivity between the studied tissues were noted. We also found that the increased immunoexpression of the GalR3 in CRC tissue correlated with the better prognosis and longer survival (p < 0.0079) of CRC patients (n = 55). The obtained results suggest that GalR3 may play the role of a prognostic factor for CRC patients. Based on data from the TCGA-COAD project deposited in the GDC Data Portal, we also found that GalR mRNA in cancer samples and the adjacent normal tissue did not correlate with immunoexpression of the GalR proteins in CRC cells and epithelial cells of the unchanged mucosa.

Objective To investigate whether galanin and its three receptors (Gal-R1, Gal-R2, Gal-R3) contribute to development of gastric cancer. Methods Preoperative and postoperative fasting venous blood samples were collected from 34 patients with gastric cancer and 13 healthy individuals. Plasma galanin contents, as well as expression levels of galanin and its receptors, were quantitatively examined in a cohort of human gastric cancer tissues and corresponding adjacent tissues. Results Statistically significantly lower galanin levels were found in the preoperative samples from patients with gastric cancer, compared with postoperative samples from these same patients, as well as with samples from healthy donors. Furthermore, galanin and Gal-R1 expression levels were dramatically reduced in gastric cancer tissues, compared with corresponding adjacent tissues, whereas Gal-R2 and Gal-R3 levels remained unchanged. Furthermore, galanin mRNA and protein expression levels in the preoperative samples from patients with gastric cancer were significantly correlated with lymph node metastasis, tumor node metastasis stage, and size of the gastric cancer. Conclusions Overall levels of galanin and Gal-R1 expression were down-regulated in patients with gastric cancer; local levels were also specifically downregulated in gastric cancer tissues. Galanin and its receptor, Gal-R1, may contribute to development of gastric cancer.

Peptide hormones and neuropeptides are complex signaling molecules that predominately function through G protein-coupled receptors (GPCRs). Two unanswered questions remaining in the field of peptide-GPCR signaling systems pertain to the basis for the diverse binding modes of peptide ligands and the specificity of G protein coupling. Here, we report the structures of a neuropeptide, galanin, bound to its receptors, GAL1R and GAL2R, in complex with their primary G protein subtypes G i and G q , respectively. The structures reveal a unique binding pose of galanin, which almost ‘lays flat’ on the top of the receptor transmembrane domain pocket in an α-helical conformation, and acts as an ‘allosteric-like’ agonist via a distinct signal transduction cascade. The structures also uncover the important features of intracellular loop 2 (ICL2) that mediate specific interactions with G q , thus determining the selective coupling of G q to GAL2R. ICL2 replacement in G i -coupled GAL1R, μOR, 5-HT 1A R, and G s -coupled β 2 AR and D1R with that of GAL2R promotes G q coupling of these receptors, highlighting the dominant roles of ICL2 in G q selectivity. Together our results provide insights into peptide ligand recognition and allosteric activation of galanin receptors and uncover a general structural element for G q coupling selectivity. The basis for the diverse peptide-binding modes and the G protein selectivity of peptide GPCRs remains elusive. Here, the authors offer a structural basis for allosteric-like agonism and G protein selectivity of a neuropeptide GPCR, galanin receptor.

Using riboprobe in situ hybridization, we studied the localization of the transcripts for the neuropeptide galanin and its receptors (GalR1–R3), tryptophan hydroxylase 2, tyrosine hydroxylase, and nitric oxide synthase as well as the three vesicular glutamate transporters (VGLUT 1–3) in the locus coeruleus (LC) and the dorsal raphe nucleus (DRN) regions of postmortem human brains. Quantitative real-time PCR (qPCR) was used also. Galanin and GalR3 mRNA were found in many noradrenergic LC neurons, and GalR3 overlapped with serotonin neurons in the DRN. The qPCR analysis at the LC level ranked the transcripts in the following order in the LC: galanin >> GalR3 >> GalR1 > GalR2; in the DRN the ranking was galanin >> GalR3 >> GalR1 = GalR2. In forebrain regions the ranking was GalR1 > galanin > GalR2. VGLUT1 and -2 were strongly expressed in the pontine nuclei but could not be detected in LC or serotonin neurons. VGLUT2 transcripts were found in very small, nonpigmented cells in the LC and in the lateral and dorsal aspects of the periaqueductal central gray. Nitric oxide synthase was not detected in serotonin neurons. These findings show distinct differences between the human brain and rodents, especially rat, in the distribution of the galanin system and some other transmitter systems. For example, GalR3 seems to be the important galanin receptor in both the human LC and DRN versus GalR1 and -2 in the rodent brain. Such knowledge may be important when considering therapeutic principles and drug development.

Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In the present review, we summarize the current data which constitute the basis of targeting GalR1, GalR2 and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors.

Spexin (SPX1) is a neuropeptide of 14 amino acids (aa), originally identified by bioinformatics, which has been implicated in various physiological functions in vertebrates via galanin receptors 2 and 3 (GALR2/3). To clarify the biological role of SPX1 in the control of reproduction in yellowtail kingfish, which is regarded as a promising species for offshore aquaculture worldwide, cDNA sequences of spx1 and six potential receptors were identified in the current study. The open reading frame of yellowtail kingfish spx1 was 363 nucleotides in size that encoded a 120-aa preprohormone, and its mature peptide was highly conserved among other species. The cDNA sequences of six GALRs (galr1a, galr1b, galr2a, galr2b, galr type 1, and galr type 2) were 1053 base pairs (bp), 1068 bp, 981 bp, 1137 bp, 1038 bp, 924 bp, which encoded G protein-coupled receptors of 350 aa, 355 aa, 326 aa, 378 aa, 345 aa, 307 aa, respectively. Tissue distribution analysis showed that spx1, galr1b, and galr2b transcripts were mainly detected in the brain. The highest mRNA levels of galr1a and galr2a were observed in the pituitary, followed by the brain and ovary. Both galr type 1 and galr type 2 were widely expressed in various tissues, with a peak level in the kidney. Moreover, all spx1 and galr genes significantly fluctuated during early ontogeny, exhibiting different expression patterns. Intraperitoneal injection of SPX1 significantly increased brain gnrh1, gnih, spx1, gal, and tac3 expression, while it inhibited gnrh2, kiss1r, and kiss2r mRNA levels. In the pituitary, SPX1 injection reduced transcript levels of gh, lhβ, and fshβ. Overall, our results have revealed the involvement of SPX1 in the reproductive functions in yellowtail kingfish.

The aim of this review is to show the involvement of the galaninergic system in neuroendocrine (phaeochromocytomas, insulinomas, neuroblastic tumors, pituitary tumors, small-cell lung cancer) and non-neuroendocrine (gastric cancer, colorectal cancer, head and neck squamous cell carcinoma, glioma) tumors. The galaninergic system is involved in tumorigenesis, invasion/migration of tumor cells and angiogenesis, and this system has been correlated with tumor size/stage/subtypes, metastasis and recurrence rate. In the galaninergic system, epigenetic mechanisms have been related with carcinogenesis and recurrence rate. Galanin (GAL) exerts both proliferative and antiproliferative actions in tumor cells. GAL receptors (GALRs) mediate different signal transduction pathways and actions, depending on the particular G protein involved and the tumor cell type. In general, the activation of GAL1R promoted an antiproliferative effect, whereas the activation of GAL2R induced antiproliferative or proliferative actions. GALRs could be used in certain tumors as therapeutic targets and diagnostic markers for treatment, prognosis and surgical outcome. The current data show the importance of the galaninergic system in the development of certain tumors and suggest future potential clinical antitumor applications using GAL agonists or antagonists.

Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer’s disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ 2 AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface.

The multitalented neuropeptide galanin was first discovered 30 years ago but initially no biologic activity was found. Further research studies discovered the presence of galanin in the brain and some peripheral tissues, and galanin was identified as a modulator of neurotransmission in the central and peripheral nervous system. Over the last decade there were performed very intensive studies of the neuronal actions and also of nonneuronal actions of galanin. Other galanin family peptides have been described, namely galanin, galanin-like peptide, galanin-message associated peptide and alarin. The effect of these peptides is mediated through three galanin receptors subtypes, GalR1, GalR2 and GalR3 belonging to G protein coupled receptors, and signaling via multiple transduction pathways, including inhibition of cyclic AMP/protein kinase A (GalR1, GalR3) and stimulation of phospholipase C (GalR2). This also explains why one specific molecule of galanin can be responsible for different roles in different tissues. The present review summarizes the information currently available on the relationship between the galaninergic system and known pathological states. The research of novel galanin receptor specific agonists and antagonists is also very promising for its future role in pharmacological treatment. The galaninergic system is important target for current and future biomedical research.

The regulatory (neuro)peptide galanin and its three receptors (GAL 1–3 R) are involved in immunity and inflammation. Galanin alleviated inflammatory bowel disease (IBD) in rats. However, studies on the galanin receptors involved are lacking. We aimed to determine galanin receptor expression in IBD patients and to evaluate if GAL 2 R and GAL 3 R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn’s disease and ulcerative colitis) expressed GAL 2 R and GAL 3 R but not GAL 1 R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL 3 R (GAL 3 R-KO) lost more body weight, exhibited more severe colonic inflammation and aggravated histologic damage, with increased infiltration of neutrophils compared to wild-type animals. Loss of GAL 3 R resulted in higher local and systemic inflammatory cytokine/chemokine levels. Remarkably, colitis-associated changes to the intestinal microbiota, as assessed by quantitative culture-independent techniques, were most pronounced in GAL 3 R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL 2 R deletion did not influence the course of colitis. In conclusion, granulocyte GAL 2 R and GAL 3 R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL 3 R loss. Consequently, GAL 3 R poses a novel therapeutic target for IBD.