Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GALR, Galanin Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_462

Synonyms

Historical Background

Galanin is a 29 amino acids (30 amino acids in human) long neuroendocrine peptide, originally isolated from porcine upper intestine in 1983 (Tatemoto et al. 1983). Subsequently, galanin was found to be expressed widely in brain and peripheral tissues. Galanin triggers cellular responses by binding to specific galanin receptors, and then the signals are transduced into intracellular effectors via G proteins. So far, there are three receptors (GalR1, GalR2, GalR3) were cloned (Branchek et al. 2000), and all of them are G-protein-coupled receptors (GPCR). The three receptors have substantial difference in their functional coupling and subsequent signaling activities, which contributes to the diversity of possible physiological effects of galanin. Galanin receptors can be found throughout the peripheral and central nervous systems (CNS) and the endocrine system, and they can regulate numerous physiological process such as sleeping regulation, feeding, nociception, nerve regeneration, learning and memory, neuroendocrine release, and gut secretion and contractility. However, the specific function of each subtype of galanin receptor remains to be fully elucidated, although great progress is being made in recent studies which newly available subtype selective agonists and antagonists and transgenic mouse models were established (Lu et al. 2008).

Agonists and Antagonists

Molecular cloning of galanin receptor subtypes has allowed design and screening for receptor subtype-specific agonists and antagonists in order to study the molecular basis of galanin actions and to develop potential therapeutic compounds. Selective galanin agonists are anticonvulsant, while antagonists produce antidepressant and anxiolytic effects in animals (Lu et al. 2005), so either agonist or antagonist ligands for the galanin receptors may be potentially therapeutic compounds in humans.

Agonists

  • Galanin: Human galanin is a 30 amino acids long, non-C-terminally amidated peptide, while galanin from all the other species is 29 amino acids long, C-terminally amidated (Tatemoto et al. 1983). Endogenous galanin is a high-affinity agonist for all three galanin receptors, GalR1, GalR2, and GalR3. The N-terminal 14 amino acids of galanin are fully conserved between different species (Lu et al. 2005). Deletion of first 16 amino acids of galanin causes the complete loss of its affinity for galanin receptors, suggesting the N-terminal 16 amino acids of galanin are critical for receptor binding.

  • Galanin 1–15 fragment: Galanin (1–15) have been shown to be highly efficacious galanin receptor agonists in vitro and in vivo, but with slightly different pharmacological profiles from that of galanin in the dorsal hippocampus.

  • Galmic and Galnon: As two small rationally designed galanin receptor agonists, both compounds have been synthesized using a tripeptidomimetic scaffold (galnon) and an oxazole scaffold (Galmic) (Saar et al. 2002). They are systemically active and substantially more resistant to degradation than the endogenous agonist galanin, making it possible to examine galanin receptor roles by systemic application intraperitoneally. The drawbacks of galnon and galmic are that they are low affinity (micromolar affinities), nonreceptor subtype selective, and interacting with other pharmacologically important targets.

  • Galanin 2–11 fragment: It was also called AR-M1896. Galanin (2–11) has been introduced as a GalR2 selective agonist. However, it also binds to GalR3 receptors with an affinity that is similar to that for GalR2, which has higher than for GalR1 receptors. Its effects have been demonstrated in the spinal cord and locus coerules.

  • Galanin-like peptide (GALP): GALP is a 60 amino acids long endogenously occurring peptide, which shares amino acid sequence homology with galanin (1–13) in position 9–21. GALP is a high-affinity agonist for both GalR1 and GalR2 receptors with slight preference for GalR2 over GalR1 (18-fold), but not GalR3.

Antagonists

  • M15, M32, M35, M40, and C7 peptides: They are synthesized chimeric high-affinity ligands, consisting of mammalian galanin (1–13) conjugated to other bioactive molecules. They act as antagonists by mediating a decrease in cyclic AMP production.

  • Spirocoumaranon (Sch 202596): It is fungal metabolite, belonging to non-peptide galanin receptor ligand. This compound was reported to act as an inhibitor on human GalR1. In addition, Sch 202596 is a low-affinity compound with additional problems precluding their further optimization.

  • 3-[(3,4-dichlorophenyl)imino]-1-(6-methoxy-3-pyridinyl)-1,3-dihydro-2Hindol-2-one: The synthesized compound has 15 nM affinity for GalR3 and shows receptor subtype selectivity and low affinity to other pharmacological targets.

The Distribution of the Three Galanin Receptors, GalR1, GalR2, and GalR3

The first known galanin receptor GalR1 was isolated from the human Bowes melanoma cell in 1994 (Habert-Ortoli et al. 1994). GalR1 was subsequently cloned from rat and mouse. Human GalR1 contains 349 amino acids, and the gene has been mapped to chromosome 18q23. GalR1 mRNA is widely expressed in the mammalian CNS, including brain and spinal cord, as well as in the gut and pancreas-derived cells such as RIN-4b. GalR2 and GalR3 were first cloned from rat hypothalamus in 1997 (Howard et al. 1997). Human GalR2 receptor contains 387 amion acids and has been mapped to chromosome 17q25.3. Unlike GalR1, GalR2 is widely distributed in almost all tissues, including in the hypothalamus, hippocampus, amygdala, and pyriform cortex, as well as in the dentate gyrus, mammillary nuclei and cerebellar cortex, and peripheral tissues such as the vas deferens, prostate, uterus, ovary, stomach, large intestine. GalR3 mRNA is relatively abundant in peripheral tissues, but expression in the CNS is more limited, been largely confined to the hypothalamus and the midbrain and hindbrain. The GalR3 is the least abundantly expressed of the galanin receptor subtypes.

In areas of the mouse brain involved in drug addiction, including the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NA), and locus coeruleus (LC), all three galanin receptors were found, with the most highly expressed of GalR1 protein in the VTA, NA, and SN, suggesting that GalR1 may play a predominant role in galanin-mediated regulation of dopamine neurotransmission. GalR1 and GalR3 protein levels are high in the LC, indicating that these isoforms may be important for galanin-mediated regulation of noradrenergic transmission during opiate withdrawal.

In the areas of gastrointestinal tract, GalR1 and GalR2 mRNAs were detected in all segments with the highest levels in the large intestine and stomach, respectively. GalR3 mRNA levels were quite low and mostly confined to the colon. The differential distribution of GalRs supports the hypothesis that the complex effects of galanin in the gastrointestinal tract result from the activation of multiple receptor subtypes (Anselmi et al. 2005).

Galanin Receptor Signaling

The galanin receptors are GPCR; therefore, cells devoted to the binding of galanin share common signal transduction components triggered by G proteins. Generally, the first step is that ligands interact with their specific galanin receptors on the membrane. Then the signal pathway mediated by the G protein is activated that initiates intracellular signal cascades. However, the three subtypes of the galanin receptors have differences in their functional coupling and subsequent signaling activities (Fig. 1, Lang et al. 2007).
GALR, Galanin Receptor, Fig. 1

Signaling pathways of galanin receptor subtypes. AC adenylate cyclase, CaCC Ca2+-dependent chloride channel, cAMP 3′,5′-cyclic adenosine monophosphate, (p)CREB (phosphorylated) cAMP response element-binding protein, DAG diacylglycerol, IP3 inositol triphosphate, MEK mitogen-induced extracellular kinase, PDK-1 phosphoinosotide-dependent protein kinase 1, PIP2 phosphatidylinositol bisphosphate, PIP3 phosphatidylinositol trisphosphate, PI3K phosphatidylinositol 3-kinase, PKB protein kinase B, PLC phospholipase C, 5HT1AR 5-hydroxtryptamine-1A receptor, GIRK G protein-coupled inwardly rectifying potassium channel (Adapted from Lang et al. 2007)

GalR1 is coupled to the Gi proteins and therefore capable of inhibiting the intracellular cAMP signaling pathway upon ligand binding. It has demonstrated that rat or human GalR1 expressed in transfected cell lines inhibits forskolin-stimulated cAMP production in a pertussis toxin (PTX)-sensitive manner. GalR1 is specifically upregulated in the locus coeruleus (LC)-like Cath, a cell line in a cyclic AMP-dependent manner. GalR1 protein and mRNA levels are also upregulated in the LC of galanin knockout mice. Also, GalR1 activates G proteins via Gßγ-subunits. Activation of GalR1 expressed in squamous carcinoma cells induces a marked and prolonged ERK1/2 activation, in this case via Gαi-subunits, leading to induction of the cell cycle arrest and suppresses proliferation in a p53-independent manner. In addition, galanin binding to GalR1 led to receptor internalization in the transfected Chinese hamster ovary (CHO) cells, which may be a mechanism for regulating the endogenous signaling cascade in native cells. Recently, Borroto-Escuela et al. (2010) have examined the possible existence of GalR1-5HT1AR (5-hydroxtryptamine-1A receptor) heteromers, indicating the existence of GalR1-5HT1A receptor–receptor interactions in the discrete brain regions. This would give rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5HT1A heteromers.

GalR2 can be coupled to different classes of G proteins, initiating two second-messenger signal cascades: the cyclic adenosine monophosphate (cAMP) and phosphoinositide signals, which are two parallel streams of intracellular events. In the pathway of phosphoinositide signal, phospholipase C (PLC) is activated. Thus, inositol phosphate hydrolysis is increased, mediating the release of Ca2+ into the cytoplasm and opening Ca2+-dependent chloride channels. In this case, GalR2 may act through Gq/11-type G proteins since the intracellular effects are not affected by PTX. In addition, it is suggested that neuronal survival enhanced by galanin is mediated by the AKT signaling pathway leading to suppression of caspase-3 and caspase-9 activity. In the pathway of cAMP signal, the forskolin-stimulated cAMP production was inhibited in CHO cells transfected with rat GalR2 and HEK-293 cells transfected with human GalR2 after galanin stimulation, and the Gi-type G proteins were suggested to be used. Furthermore, both GalR1 and GalR2 activations inhibit cyclic AMP-responsive element-binding (CREB) protein. However, there are somewhat controversial points on this pathway. It is also supported that GalR2 is coupled to a Go-type G-protein, activating MAPK in a PKC-dependent fashion or to a G12/13-type G-protein, activating RhoA.

GalR3 appears to couple to a Gi/o-type G-protein to stimulate the activation of an inward K+ current. In addition, a Gi-type G-protein was also reported to be involved in GalR3 signaling. However, the detail signaling pathways mediated by GalR3 are still poorly understood. New molecular tools, such as application of subtype-specific antisense reagents and gene knockout approaches, will clarify our understanding of the role of galanin receptor subtypes in galaninergic signaling.

Effects of GalRs in NS

Galanin and its receptors are widely expressed in the CNS and peripheral nervous system (PNS), indicating the numerous physiological effects of GalRs. The three galanin receptors have been found to be involved in the control of feeding, alcohol intake, seizure threshold, cognitive performance, and mood and pain threshold (Mitsukawa et al. 2008).

Learning and Memory

The effects of galanin participating in the learning and memory have been shown in many studies. It is generally accepted that the ability to perform learning and memory tasks will be impaired if too much galanin in the hippocampus or lateral ventricles of rats. This effect can be blocked by GalR2 antagonist M40. However, we should also be aware that the results have some controversy. In some recent testing of a GalR2-KO strain (Lang et al. 2007), the mutant mice were not significantly different to wild-type littermates on the cognition tests (Ogren et al. 1996). This suggests that GalR2 may be not centrally involved in learning and memory. But it cannot rule out the possibility that galanin levels have not reached sufficient levels during the behavioral tasks, or compensatory developmental changes in the other galanin receptors (Ogren et al. 1996). Further experiments should be able to address these possibilities.

Mood Regulation and Alcohol Intake

Galanin was found to be coexpressed with noradrenaline in the noradrenergic neurons in the locus coeruleus (LC) and with serotonin in the serotonergic neurons in the dorsal raphe nucleus (DRN) (Lu et al. 2005). The overactivity of the LC noradrenergic neurons leads to suppression of the firing of the DRN serotonergic neurons, thus causing depression. It was suggested by Lu et al. (2005) that GalR2 agonists, like blockers of serotonin (SSRIs), may be effective in the treatment of major depression. Also, GalR3 antagonists have anti-depressant-like activity. The GalR3 subtype selective antagonists had been synthesized, and they were confirmed to be active in some anxiety or acute antidepressant models. In addition, GalR3 has been shown a significant association with alcoholism, but there was no effect of GalR1 or GalR2 haplotypes on alcoholism risk. Thus, Mitsukawa et al. (2008) indicated that development of galanin receptor antagonists, in particular GalR3 antagonists, might be a breakthrough in the addiction relevant field.

Feeding

It is reported that galanin had the ability to induce food intake strongly (Leibowitz 2005). The choice of food preference – if protein, carbohydrates, and fat are available – is fat first and carbohydrate second. It also suggested that the food preference was caused by activating the process of ingestion rather than controlling satiety feeling. Although all three galanin receptor subtypes are present in brain regions important for galanin-stimulated feeding, it is indicated that the rat feeding response was attributed to either GalR1 or an unidentified GalR rather than to GalR2 and GalR3. Furthermore, the studies on GalR1 null mutation carrying mice showed that GalR1 mediated the important effects that are required for glycemic control and body weight control (Zorrilla et al. 2007).

Pain

Galanin and its three receptors are expressed in both sensory and spinal cord interneurons. Also, nerve injury such as axotomy can lead to a rapid high-level expression of galanin in the sensory ganglia. The expression profiles of galanin and the three receptors indicate that they may play a key gatekeeper role in pain signaling (Wiesenfeld-Hallin and Xu 2001). Galanin has double-eged function in many pain models. It can both act as inhibitory or excitatory mediator, depending on the circumstance such as the nature of stimulus of the nociceptive (thermal, mechanical, chemical), the acute or chronic state, and the concentration of galanin available to act on the nociceptive afferent nerves. It is suggested that low galanin doses can escalate and high doses suppress pain. The GalR2-mediated depolarizing effects may contribute to pain sensation, while GalR1-mediated hyperpolarization of the sensory and interneurons are responsible for the analgesic effect. Therefore, GalR1 agonists may be the potential candidates for systemic or intrathecal use in pain therapy.

Neuronal Injury

The expression of galanin is strongly increased in mRNA or protein levels after neuronal injury, suggesting a trophic role for galanin. Indeed, galanin acts as a survival- and growth-promoting factor for different types of neurons in the peripheral and central nervous system. For example, the decrease of galanin level was observed in many damage models of different brain region, including the cut or extrusion of motor and sensory neurons, traverse of central nerve, focal cerebral ischemia. Also, GalR2 was suggested to be related to the survival of hippocampal neuron and injured brain (O’Meara et al. 2000). It is reported that the selective GalR2 peptide agonist AR-M1896 counteracts a number of morphological alterations induced by glutamate toxicity in neuronal hippocampal cells.

Anxiety

Galanin and receptors were found to be expressed in brain areas relevant to emotional behavior, such as the amygdala and the BNST (the bed nucleus of the stria terminalis). Its coexistence with noradrenaline (NE) and serotonin in relevant neural pathways were also discovered. Thus, the roles of galanin and its receptors in animal models of anxiety were concerned. Behavioral studies of both GalR1- and GalR2-KO mouse strains suggested a role for galanin in regulating anxiety-related behaviors. In addition, it is reported that galanin express the activity of anti-anxiety via GalR1 under the relatively high pressure. Also, there are other experiments indicated that GalR2 and GalR3 have been involved in the process of anti-anxiety. However, the concrete process concerning the three receptors has to be further research.

Effects of Galanin and GalRs for Many Pathological Diseases

Epilepsy

During the past decade, the growing evidences have been suggesting that galanin is in fact a powerful inhibitor of seizure activity. In the hippocampus, galanin inhibits both acetylcholine release and postsynaptic cholinergic functions. It was reported that both acetylcholine release and postsynaptic effects of pilocarpine and acetylcholine were increased in GalR1 null mutation mouse, thus promoting seizures (Fetissov et al. 2003). The duration of epilepticus can be significantly shortened by the pretreatment of galanin, but this effect can be reversible by the injection of a GalR1 antagonist, M35. Moreover, M35 alone promotes the establishment of seizures and prolongs their duration. Collectively, galanin can affect the maintenance phase of seizures possibly via GalR1. Pharmacological application of galanin agonists should be a potently useful antiepileptic.

Alzheimer’s Disease

Alzheimer’s disease is characterized by the progressive degeneration of the cholinergic/galaninergic neurons and the cognitive function losing gradually. Learning and cognitive performance of rodents were shown to be impaired after intrahippocampal- or intracerebroventricularly (i.c.v)-injected galanin (Rustay et al. 2005). This is in line with the overexpression of galanin in Alzheimer’s disease. Also, the expression of galanin receptor was found to be higher in Alzheimer’s disease afflicted brains. GalR1 antagonists, as a cognitive enhancer, might help the treatment of the Alzheimer’s disease since they would disinhibit the release of acetylcholine. In addition, GalR2 agonists were suggested to run roles in neuroprotection and neurogenesis. Thus, GalR2 agonists are also expected to be useful to cognitive disorders of neurodegenerative etiology.

Tumors

The expressions of galanin and galanin receptors have been detected in several tumors such as pancreatic, hypothalamic, and pituitary tumors; small cell lung carcinoma; and colon cancer isolates (Mitsukawa et al. 2008), which prompts that galanin can be involved in many tumor pathophysiological process. For example, galanin has mitogenic effects on human pancreatic cancer cells and stimulated the proliferation and prolactin secretion of rat pituitary tumor cells in vitro. Therefore, galanin and galanin receptor expressions are becoming increasingly used markers for certain tumors. In head and neck squamous cell carcinoma (HNSCC), signal mechanism has also been studied, which GalR1 and GalR2 were revealed to act as tumor suppressors in a p53-independent manner. GalR1 or GalR2 induces cell cycle arrest and suppresses proliferation in HNSCC, and GalR2 can also induce apoptosis (Kanazawa et al. 2010). Indeed, galanin has been clinically used in pancreatic tumor therapy.

Diabetes

Galanin has been detected in pancreatic islet cells in several species. There are a large number of galanin-like immunoreactive (galanin-LI) cells in both the peripheral and central regions of the islet of Langerhans of normal rat pancreas, but the galanin-LI cells are significantly less in diabetic ones. In addition, the concentration of insulin in humans was shown to be suppressed after galanin injection. Therefore, the positive correlation of galanin with diabetes is expected. It was suggested that the specific mechanism for galanin effect was involved in GalR1 since the GalR1 agonist M40 can suppress glucose-stimulated insulin release. GalR3 was also reported to be involved in this process.

The Evolution of GalR

To obtain insights into the evolution of GalRs, Liu et al. (2010) have searched the genomes of the deuterostomes by extensive BLAST survey and phylogenetic analyzes. Typical GalR1 and GalR2 genes were found from fish to human; however, GalR3 were only found in some mammalian. Interestingly, two GalR1 genes were found in fish, including F. rubripes, T. nigroviridis, and D. rerio, and two GalR2 genes were presence in G. gallus. These indicate that the GalR1 and GalR2 gene duplication events occurred in fish and chick, respectively. GalR2 and GalR3 share similar genomic structures, which most of them are composed of two exons and one intron. However, most of GalR1 are composed of three extrons and two introns. Typical GalR genes were not detected in the genomic databases of invertebrate deutserotomes, including S. purpuratus, C. intestinalis, and amphioxus, but three GalR1/Alstr homologs and two GalR1/Gpr151 homologs in amphioxus, two GalR1/Gpr151 homologs in sea squirt, and one GalR1/Gpr151 homolog in sea urchin were identified. It is highly possible that the GalR genes in vertebrates may evolve from the homologous genes of GalR1/Alstr/Gpr151 in invertebrate deuterostomes. Also, GalR3 genes may be the products of GalR2 duplication during evolution, while GalR2 genes may evolve from GalR1.

Summary

The widely distribution of galanin and GalRs in the CNS and in the PNS and various organs demonstrates that the galanin and GalRs play key roles in numerous physiological functions such as seizure, learning, nociception, nerve regeneration, food intake, and reproduction. However, there is controversy concerning some certain physiological functions of galanin and GalR, such as learning and memory, anxiety behavior modulation. With more galanin receptor knockout mice are got, the biological effects mediated by activation of distinct galanin receptor subtypes in various organ systems would be more clear. The search for agonists and antagonists of specific GalRs will promote the research and application of GalRs in the drug target.

Notes

Acknowledgments

This work was supported by Program for New Century Excellent Talents in University to Zhenhui Liu (No. NCET-08-0501), the Ministry of Science and Technology (MOST) of China (No.2008AA092603 and 2008AA09Z409) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 2009–1001).

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Marine Biology, Key Laboratory of Marine Genetics and BreedingOcean University of ChinaQingdaoChina
  2. 2.Institute of Evolution and Marine BiodiversityOcean University of ChinaQingdaoChina