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. 2020 Nov 2;15(2):269–275. doi: 10.1007/s12079-020-00590-3

An assembly of galanin–galanin receptor signaling network

Lathika Gopalakrishnan 1,2,3, Oishi Chatterjee 1,3,4, Chinmayi Raj 5, Deepshika Pullimamidi 5, Jayshree Advani 1,8, Anita Mahadevan 6,7, T S Keshava Prasad 3,✉
PMCID: PMC7990979  PMID: 33136286

Abstract

The galanin receptor family of proteins is present throughout the central nervous system and endocrine system. It comprises of three subtypes—GalR1, GalR2, and GalR3; all of which are G-protein-coupled receptors. Galanin predominantly acts as an inhibitory, hyper-polarizing neuromodulator, which has several physiological as well as pathological functions. Galanin has a role in mediating food intake, memory, sexual behavior, nociception and is also associated with diseases such as Alzheimer’s disease, epilepsy, diabetes mellitus, and chronic pain. However, the understanding of signaling mechanisms of the galanin family of neuropeptides is limited and an organized pathway map is not yet available. Therefore, a detailed literature mining of the publicly available articles pertaining to the galanin receptor was followed by manual curation of the reactions and their integration into a map. This resulted in the cataloging of molecular reactions involving 64 molecules into five categories such as molecular association, activation/inhibition, catalysis, transport, and gene regulation. For enabling easy access of biomedical researchers, the galanin–galanin receptor signaling pathway data was uploaded to WikiPathways (https://www.wikipathways.org/index.php/Pathway:WP4970), a freely available database of biological pathways.

Electronic supplementary material

The online version of this article (10.1007/s12079-020-00590-3) contains supplementary material, which is available to authorized users.

Keywords: Galaninergic neuromodulatory system, NetPath, Post-translational modifications, Protein–protein interactions, Neuromodulation

Introduction

The galaninergic neuromodulatory system was first discovered 30 years ago, in the porcine intestinal extracts by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden. (Wynick et al. 2001). The galanin receptor family, widely expressed in the brain and the peripheral tissues comprises of three subtypes, GalR1, GalR2, and GalR3. Although several bioactive peptides such as galanin-like peptide, galanin-message associated peptide and alarin have been reported to be a part of the galanin family, galanin is the principle molecule of the galaninergic system. The galanin receptors are seven transmembrane-domain receptors belonging to the G-protein coupled receptor family (GPCR). Galanin receptors, like other GPCRs, show substantial differences in the functional coupling that eventually initiate multiple downstream signaling cascades such as, inhibition of cAMP/PKA (GalR1, GalR3) and stimulation of phospholipase C (GalR2). Depending on the location of expression, ligand, and the G-protein repertoire, galanin exerts a broad range of physiological roles in normal and pathological conditions.

The genes, Galanin/GMAP prepropeptide (GAL) and galanin-like peptide (GALP) encode for the galanin family of peptides. The sequences of these genes are highly conserved in mammals. The GAL gene which is located at chromosome 11q 13.33, encodes for a preprogalanin protein, consisting of 60 amino acids. The enzymatic cleavage of preprogalanin protein forms the mature neuropeptide. The mature neuropeptide-galanin contains 29 amino acid residues. Galanin is named after the presence of an N-terminal glycine residue and a C-terminal alanine residue. However, an exception to this is found in humans where galanin has a C-terminal nonamidated serine and is composed of 30 amino acids (Schmidt et al. 1991; Branchek et al. 2000). In the brain, galanin is produced by the amygdala and hypothalamus, which are the centers regulating emotion and food intake. Galanin is also found to be expressed in the spinal cord, endocrine system, gastrointestinal tract, keratinocytes, eccrine sweat glands and around blood vessels (Kofler et al. 2004). The second member of the galanin peptide family, galanin-like peptide (GALP), is a 60 amino acid long peptide originally discovered as an endogenous ligand for galanin receptors present in the porcine hypothalamus and gastrointestinal tract (Ohtaki et al. 1999).

The wide range of the receptors and the ligands reflect multiple functions of galanin signaling. Specific galanin receptor stimulation by its endogenous ligands is known to be responsible for a range of functions including nociception (Liu and Hokfelt 2002), arousal or sleep (Sherin et al. 1998; Steininger et al. 2001), cognition (Kinney et al. 2002; McDonald et al. 1998), metabolic and osmotic homeostasis (Crawley 1999; Gundlach 2002; Landry et al. 2000). Studies suggest the role of galanin in the amygdala, towards addictive behavior such as repeated alcohol intake (Morilak et al. 2003). A study by Lim et al., corroborate the role of galaninergic neurons from the ventrolateral preoptic nucleus of the hypothalamus in maintaining sleep continuity and sleep regulation. The number of galanin-immunoreactive intermediate nucleus neurons is a marker of sleep fragmentation (Lim et al. 2014). The disturbance of the galaninergic system is also known to be associated with diseases such as Alzheimer’s disease, epilepsy, diabetes mellitus and chronic pain (Lang et al. 2007; Branchek et al. 2000; Juhasz et al. 2014). Studies have shown that injecting galanin into the hypothalamic paraventricular, lateral and ventromedial nuclei and the central nucleus of the amygdala leads to an increase in feeding response and total caloric intake (Karatayev et al. 2009). Thus, galanin acts in increasing the preference for a high-fat diet by activating feeding behavior rather than suppressing satiety (Leibowitz et al. 2004). Stimulation of different galanin receptors are also known to be associated with antagonistic effects like in the case of depression; stimulation of GalR2 has an anti-depressant effect whereas stimulation of GalR1 and GalR3 has depressive effects (Millon et al. 2017; Le Maitre et al. 2011; Brunner et al. 2014). Additionally, the galanin receptors form heteroreceptor complexes such as the GalR1–GalR2 leading to conformational changes, which causes the GalR1 protomer to show a preferential binding affinity to galanin fragment (1–15) than galanin. This binding results in increased Gi/o mediated signaling, which leads to enhanced reduction of AC activity and CREB, causing depressive effects (Borroto-Escuela et al. 2014). Galanin receptor (GalR1) also forms heterodimers with serotonin receptors as well as neuropeptide Y Y1 receptors and their role in depression are targeted in the development of drugs for treating depression (Borroto-Escuela et al. 2010; Narvaez et al. 2016; Fuxe et al. 2012).

As a complete and integrative map of galanin is not yet available, we attempted to construct a galanin receptor signaling map by arranging the molecular reactions with available experimental evidence in the form of a pathway. This map will be useful for understanding the pleiotropic effect of galanin in different tissues/organs. It will also provide insights into the relationship between the galaninergic system and the diverse pathological states, which will facilitate pharmacological research and future targeted treatment.

Methodology

An extensive literature search was performed using PubMed to screen the processes that are involved in the stimulation of galanin receptors. We classified the biochemical reactions into five categories such as (1) molecular association, (protein–protein interactions), (2) catalysis (post-translational modification, cleavage, and binding), (3) translocation/transport of proteins between subcellular compartments, (4) activation/inhibition, and, finally, (5) gene regulation at the mRNA and/or protein level (both up- and down-regulation) (Kandasamy et al. 2010). We followed the categorization of the annotation adhering to the NetPath criteria as previously defined in similar articles on serotonin (Sahu et al. 2018), oxytocin–oxytocin receptor (Chatterjee et al. 2016), macrophage migration inhibitory factor (Subbannayya et al. 2016), oncostatin M (Dey et al. 2013), BDNF/p75NTR (Sandhya et al. 2013), and RANKL/RANK (Raju et al. 2014) pathways. The relevant reactions were then manually annotated from the research articles that were first reviewed internally and then externally by a neuropathologist.

We annotated information about the cell lines or model animals used for the study, type of the experiment—in vivo or in vitro, subcellular localization of proteins and information on site and residue for post-translational modifications (PTM), reported in literature. The reactions relevant to galanin mediated signaling were connected to generate a pictorial representation in the form of a map using PathVisio, an open-source, free pathway drawing tool (van Iersel et al. 2008). The generated map was then exported to WikiPathways, a freely available pathway resource (https://www.wikipathways.org/index.php/WikiPathways).

Results

The literature curation, using specific query terms such as: “galanin OR GMAP prepropeptide” OR “GAL” OR “ETL8-GMAP” OR “GALN” OR “GLNN” OR “GMAP” OR “GAL” OR “galanin receptor 1” OR “GALR1” OR “GALNR” OR “GALNR1” OR “galanin receptor 2” OR “GALR2” OR “GAL2-R” OR “GALNR2” OR “GALR-2” OR “galanin receptor 3” OR “GALR3” AND (“signaling” OR “pathway” OR “signalling”), provided 2140 research articles containing information about galanin receptor signaling. Amongst these, 93 articles which had annotatable information were selected for manual curation. We annotated the signaling pathway information following the NetPath annotation criteria, as described previously. The annotated articles generated a total of 12 catalysis reactions, 12 gene regulation reactions at the transcriptional level and 21 at the translational level, 13 activation/inhibition reactions, 3 protein translocation reactions, and 3 molecular association reactions (See also Supplementary Table 1). The galanin signaling pathway map representing all the enzymes, reactions, regulators and interactors is shown in Fig. 1 and is freely available in the public domain (https://www.wikipathways.org/index.php/Pathway:WP4970). The data is presented in BioPAX level 3 format (OWL), a standard community exchange format (Demir et al. 2010). The pathway data can be downloaded from the WikiPathways website in PNG, PDF and SVG image formats as well as the gene lists in .txt format (Kelder et al. 2009).

Fig. 1.

Fig. 1

Open in a new tab

A schematic representation of the biochemical reactions induced by the galanin–galanin receptor system. The pathway map depicts the signaling cascades upon stimulation by galanin represented as the downstream molecular associations, enzyme catalysis reactions, translocation events, gene and/or protein regulation events. Legends describe the reaction events in the map

All three galanin receptors have different molecular structures and functions, hence their signal transduction mechanisms follow different routes. As emerging from available evidence, the biological stimulation of GalR1 is associated with adenylyl cyclase and cAMP production (Habert-Ortoli et al. 1994, Wang et al. 1998b). As depicted in the map, also shown in many studies; GalR1 activation induces adipogenesis by stimulating the mitogen associated protein kinase (MAPK1/MAPK3) activity via pertussis toxin (PTX) sensitive Gα inhibitory-subunits (Gi) in a Ras/Raf-dependent manner (Crespo et al. 1994; Shefler et al. 1999). The activation of GalR2 by various ligands such as galanin-like peptide and galanin leads to the stimulation of the cascades under the PTX-insensitive Gαq/11 class of G-proteins. This triggers the phospholipases, which increase the hydrolysis of inositol phosphate, mediating the release of Ca2+ from the sarcoplasmic/endoplasmic reticulum to the intracellular spaces later opening the Ca2+-dependent channels (Wang et al. 1998a; Pang et al. 1998). Another interesting observation of GalR2 stimulation is the activation of neuronal development, observed mostly through the AKT pathway (Ding et al. 2006). GalR2 illicit another range of cascades, such as the MAPK1/3 dependent cell proliferation and AKT dependent cell survival. Both of these reactions are mediated by an activated Rap1 (TERF2IP) by GTP binding (Banerjee et al. 2011). Also, GalR2 stimulates MAPK pathways by activating PKC via G0 proteins (Badie-Mahdavi et al. 2005; Wang et al. 1998b). Additionally, GalR2 plays role in the activation of small GTPase protein in the Rho family; RhoA through G12/13 class of G proteins (Wittau et al. 2000).

GalR1 and GalR2 are among the most studied of the three receptors, while the signaling system of GalR3 is ill-defined. GalR3 mainly exerts its function through the PTX-sensitive Gi/o-type G protein similar to GalR1. However, its signaling leads to the inhibition of adenylyl cyclase that finally perturbs the phosphorylation of CREB, unlike GalR1 (Kolakowski et al. 1998; Smith et al. 1998). GalR1 and GalR2 mediated signaling cascades show certain similar biological outcomes such as induction of apoptosis, adipogenesis, inhibition of cell proliferation and regulation of nociception (Berger et al. 2004, Kim and Park 2010). These events are mediated through the MAPK and AKT pathways in association with apoptotic proteins such as CASP12 and CASP8 (Li et al. 2017; Tofighi et al. 2008). These outcomes are also achievable through the alteration in the expression of cyclin-dependent kinase inhibitor proteins such as CDKN1B and CDKN1C (Kanazawa et al. 2009, 2014). The anti-depressive activity of the galaninergic system is unraveled by the heterotrimer formation of GalR1–GalR2-5-HT1A receptors. This interaction causes conformational changes in galanin recognition sites altering the galanin binding affinities that block the resultant increased activation of Gi/o linked to each of the galanin receptors and an increased inhibition of adenylyl cyclase as well as stimulation of MAPK activity (Fuxe et al. 2012).

It is to be noted that certain physiological outcomes of galanin receptor stimulation are specific to a receptor subtype. For example, the activation of GalR1 results in ameliorating insulin resistance by facilitating adiponectin release and inducing the translocation of glucose transporter GLUT4 from the intracellular compartment to the cell surface. This effect often occurs by triggering the AKT/AS160 cascade and by inhibiting the release of C-reactive protein (Zhang et al. 2016). The pathway map portrays the signaling mechanisms of galanin stimulation to be substantially different depending on the receptor subtype, cellular conditions, the extent of expression of the ligands and the downstream secondary messengers.

The pleiotropic effects of galanin are not only observed in the normal physiological conditions, but also under pathological conditions. An upregulation of galanin production and galanin receptor binding sites has been observed in the post-mortem studies of the brain of Alzheimer’s disease victims; that was later discovered to be associated with neuroprotective profile of galanin (Counts et al. 2009, 2010). Similarly, galanin levels were found to be downregulated in an inflammatory skin disease-psoriasis, indicating the relevance of galanin in the cutaneous pathophysiology (Gudjonsson et al. 2009). The galanin–galanin receptor signaling pathway, being involved in a wide-range of physiological activities, will provide several potential candidates for drug targeting in several disorders and diseases.

Conclusions

The availability of galanin–galanin receptor signaling map will enhance our understanding of the role of various molecules involved in the regulation of this pathway in normal and in various physiological states. Moreover, this map will help elucidate biological functions by targeting the interactors and the downstream effectors of galanin-associated signaling and galanin-related disorders. This resource will help translate the available information for the discovery of further molecules in this network and develop novel pharmacological strategies for galanin related diseases.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1 (66.6KB, xlsx)

Annotated reactions associated with galanin receptor signaling in humans and other mammals categorized into A. Activation/Inhibition B. Enzyme catalysis C. Molecular association D. Transport and E. Gene regulation (XLSX 66 kb)

Acknowledgements

We thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka for the support to the Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme in Multiomics Technology (BiSEP GO ITD 02 MDA 2017). We thank the Department of Biotechnology, Government of India for research support to the Institute of Bioinformatics (IOB), Bangalore. LG and OC are recipients of DST INSPIRE Senior Research Fellowship from the Department of Science and Technology (DST), Government of India.

Abbreviations

GAL

Galanin

GalR

Galanin receptor

GALP

Galanin-like peptide

CNS

Central nervous system

GPCR

G-protein coupled receptor

CREB

cAMP response element-binding protein

PKA

Protein kinase A

MAPK

Mitogen activated protein kinase

PPIs

Protein–protein interactions

PTM

Post-translational modification

cAMP

Cyclic adenosine monophosphate

BioPAX

Biological pathway exchange

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Contributor Information

Lathika Gopalakrishnan, Email: lathika@ibioinformatics.org.

Oishi Chatterjee, Email: oishi@ibioinformatics.org.

Chinmayi Raj, Email: chinmayigraj@gmail.com.

Deepshika Pullimamidi, Email: deepshikag.puli@gmail.com.

Jayshree Advani, Email: jayshree.ibioinformatics@gmail.com.

Anita Mahadevan, Email: mahadevananita@gmail.com.

T. S. Keshava Prasad, Email: keshav@yenepoya.edu.in

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1 (66.6KB, xlsx)

Annotated reactions associated with galanin receptor signaling in humans and other mammals categorized into A. Activation/Inhibition B. Enzyme catalysis C. Molecular association D. Transport and E. Gene regulation (XLSX 66 kb)

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