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Galanin
Galanin
Galanin
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GAL
Identifiers
AliasesGAL, GAL-GMAP, GALN, GLNN, GMAP, ETL8, galanin and GMAP prepropeptide
External IDsOMIM: 137035; MGI: 95637; HomoloGene: 7724; GeneCards: GAL; OMA:GAL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

51083

14419

Ensembl

ENSG00000069482

ENSMUSG00000024907

UniProt

P22466

P47212

RefSeq (mRNA)

NM_015973

NM_010253
NM_001329667

RefSeq (protein)

NP_057057

NP_001316596
NP_034383

Location (UCSC)Chr 11: 68.68 – 68.69 MbChr 19: 3.46 – 3.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Galanin
Identifiers
CAS Number
ChemSpider
  • none
ChEMBL
Chemical and physical data
FormulaC146H213N43O40
Molar mass3210.571 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Galanin is a neuropeptide encoded by the GAL gene,[5] that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.[6]

Much of galanin's functional role is still undiscovered. Galanin is closely involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor.[7] Galanin neurons in the medial preoptic area of the hypothalamus may govern parental behaviour.[8] Galanin is linked to a number of diseases including Alzheimer's disease, epilepsy as well as depression, eating disorders, cancer, and addiction.[9][10] Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon axotomy in the peripheral nervous system as well as when seizure activity occurs in the brain. It may also promote neurogenesis.[6]

Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide[11] and as such inhibits neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine, serotonin, and norepinephrine, and also with other neuromodulators such as neuropeptide Y, substance P, and vasoactive intestinal peptide.[12]

Discovery

[edit]

Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden[13] using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine.[14] The structure of galanin was determined in 1983 by the same team, and the cDNA of galanin was cloned from a rat anterior pituitary library in 1987.[13]

Tissue distribution

[edit]

Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the hypothalamus, with lower levels in the cortex and brainstem. In the hypothalamus, it is for example found in the ventrolateral preoptic nucleus where it has sleep-promoting function. Within the brain, galanin has also been found in the ventral forebrain and amygdala.[15] Along with this, the immune reaction of galanin in the brain is centered in the hypothalamopituitary.[16] Gastrointestinal galanin is most abundant in the duodenum, with lower concentrations in the stomach, small intestine, and colon.[17] Galanin is also expressed in the skin where is serves anti-inflammatory functions.[18] Specifically, it has been found in keratinocytes, eccrine sweat glands, and around blood vessels.[18] Galanin has been found in endocrine tumors.[19] Within gastric cancer cells, galanin has been found to have a tumor suppressive role, but hypermethylation has been shown to stop its tumor suppressive properties.[20]

Structure

[edit]
Endogenously occurring galanin sequences
Species 1 6 11 16 21 26 !
Pig G W T L N S A G Y L L G P H A I D N H R S F H D K Y G L A *
Human G W T L N S A G Y L L G P H A V G N H R S F S D K N G L T S **
Cow G W T L N S A G Y L L G P H A L D S H R S F Q D K H G L A *
Rat G W T L N S A G Y L L G P H A I D N H R S F S D K H G L T*
* C-terminal amide ** C-terminal free acid

Galanin is a peptide consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as prepro galanin, which is encoded by the GAL gene.[5] The sequence of this gene is highly conserved among mammals, showing over 85% homology between rat, mouse, porcine, bovine, and human sequences.[12] In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein.

These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin and other regulatory peptides in their autologous species.[21]

The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of prepro galanin.[14] The other two peptides, galanin-like peptide (GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the prepro GALP gene. GALP and alarin are produced by different post-transcriptional splicing of this gene.[22]

Galanin
Identifiers
SymbolGalanin
PfamPF01296
InterProIPR008174
PROSITEPDOC00673
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Galanin message associated peptide (GMAP)
Identifiers
SymbolGMAP
PfamPF06540
InterProIPR013068
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Receptors

[edit]

Galanin signalling occurs through three classes of receptors, GALR1, GALR2, and GALR3, which are all part of the G protein-coupled receptor (GPCR) superfamily. Galanin receptors are expressed in the central nervous system, in the pancreas, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons.[6] Experiments into the function of the receptor subtypes involve mostly genetic knockout mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.[6]

Clinical characteristics

[edit]

Appetite

[edit]

Injections of galanin into the lateral ventricle or directly into the hypothalamus creates the urge to feed, with a preference for eating fats.[19] Galanin also regulates glucose metabolism and can potentially alleviate symptoms of Diabetes Type II due to its interaction with insulin resistance.[23] Galanin is an inhibitor of pancreatic secretion of insulin.[19]

Addiction

[edit]

Galanin plays a role in addiction regulation.[24] It is involved in repeated alcohol intake.[19] Along with addiction to alcohol, galanin has been shown to play a role in addiction to nicotine and opiates.[24]

Alzheimer's disease

[edit]

One of the pathological features of the brain in the later stages of Alzheimer's disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergic neurons.[25] Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in postmortem brains of Alzheimer's patients.[6][22] The cause and role of this increase is poorly understood.[25][26]

It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive function in patients by decreasing the amount of acetylcholine available to these neurons.[6][25]

A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid toxicity.[27]

Cognitive performance

[edit]

Galanin participates in cognitive performance and has been shown to weaken learning and cognition.[19]

Depression

[edit]

Noradrenaline and serotonin, two neurotransmitters involved in depression, are both co-expressed and modulated by galanin, suggesting that galanin plays a role in the regulation of depression.[15] Stimulation of the Gal1 and Gal3 receptors result in depression-like behaviors, whereas stimulation of the Gal2 receptor results in reduced depression-like behaviors.[15] Currently, one of the potential mechanisms for this is that galanin stimulates the hypothalamus-pituitary-adrenal axis, which leads to an increase in glucocorticoid secretion.[15] Increased levels of glucocorticoid hormones is common in those who suffer from depression.[28]

Endocrine

[edit]

Galanin inhibits the secretion of insulin and somatostatin and stimulates the secretion of glucagon, prolactin, somatotropin, adrenocorticotropin, luteinizing hormone, foliculotropin, growth hormone-releasing hormone, hypothalamic gonadotropin-releasing hormone, and corticotropin-releasing hormone.[29]

Epilepsy

[edit]

Galanin in the hippocampus is an inhibitor of glutamate but not of GABA. This means that galanin is capable of increasing the seizure threshold[6] and, therefore, is expected to act as an anticonvulsant. To be specific, GalR1 has been linked to the suppression of spontaneous seizures.[30][31] An agonist antiepileptic drug candidate is NAX 5055.[32][33]

In development

[edit]

It has been shown that galanin plays a role in the control of the early post-natal neural development of the dorsal root ganglion (DRG).[13] Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P. This suggests that the cell loss by apoptosis that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.

Pain and neuroprotection

[edit]

Galanin plays an inhibitory role in pain processing,[34] with high doses having been shown to reduce pain.[19] When galanin is added to the spinal cord, neuropathic pain is reduced.[35] Along with this, galanin is believed to be effective in reducing spinal hyperexcitability.[35] Sensory neurons increasingly release galanin when they are damaged.[35] An increase in the concentrations of galanin are also believed to be for neuroprotective reasons and lead to promoted neurogenesis.[19] GalR2 activation is believed to mediate the survival role galanin plays in the dorsal root ganglion.[34]

Parental role in mice

[edit]

Galanin-expressing neurons in the medial preoptic area of the brain are responsible for regulating aggression towards pups by male mice.[8]

Galanin-expressing neurons in the medial preoptic area are remodelled during pregnancy. Estrogen and progesterone genomic receptors in galanin (Gal)-expressing neurons control discrete aspected of plasticity.[36]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Galanin

View on Grokipedia
from Grokipedia
Galanin is a neuroendocrine encoded by the GAL gene on 11q13.2 in humans, serving as a precursor that is proteolytically processed into the mature 30-amino-acid galanin and the galanin message-associated (GMAP). Widely expressed in the central and peripheral nervous systems, as well as the , , , and urogenital tract, galanin acts primarily as a neuromodulator and , binding to three G protein-coupled receptors (GALR1, GALR2, and GALR3) to exert diverse effects on physiological processes. Discovered in 1983 in extracts from the porcine intestine, galanin has since been identified across mammals, with its mature form featuring a conserved N-terminal region critical for receptor binding and a C-terminal amidation that enhances its bioactivity. In the , galanin is prominently localized in regions such as the , , and , where it modulates synaptic transmission, , mood, and epileptic activity. Peripherally, it influences gastrointestinal , pancreatic —including suppression of insulin release in animal models—and adrenal functions. Galanin's roles extend to , where it promotes feeding and fat storage, contributing to obesogenic effects, while also regulating by inhibiting signaling in sensory neurons. Additionally, it participates in osmotic regulation, , and reproductive behaviors, such as via neurons in the medial . The peptide's therapeutic potential has garnered attention due to its involvement in conditions like mood disorders, where it exhibits anxiolytic and antidepressant-like effects depending on brain region, and metabolic syndromes linked to its impact on insulin sensitivity and energy expenditure. Recent research as of 2025 has highlighted galanin's role as a biomarker in cancers such as endometrial and colorectal, and in spinal cord regeneration. GMAP, the co-processed peptide, demonstrates antifungal activity and may support innate immunity. Structural studies, including AlphaFold predictions, reveal galanin's five alpha helices and two beta strands, underscoring its evolutionary conservation and receptor interaction mechanisms.

Discovery and Molecular Biology

Discovery

Galanin was first identified in the late amid a burgeoning era of research, during which Viktor Mutt's laboratory at the in pioneered the isolation of bioactive peptides from gastrointestinal tissues. This period followed key discoveries such as (VIP) in 1970 and cholecystokinin (CCK) in the early , highlighting the gut-brain axis and the prevalence of regulatory peptides with amidated C-termini. Mutt's team, leveraging advances in and techniques, sought to uncover novel hormones influencing digestion and neural functions, setting the stage for galanin's emergence as a multifunctional . In 1978, Katsuya Tatemoto and Viktor Mutt developed an innovative chemical assay to detect polypeptide hormones ending in α-amidated residues. This method, which involved enzymatic release of C-terminal fragments, conversion to fluorescent derivatives, and (HPLC) separation, enabled sensitive purification without reliance on specific bioactivities. The approach was instrumental in identifying several previously unknown peptides and was applied in 1983 to porcine intestinal extracts for the isolation of galanin. The peptide was provisionally characterized by its C-terminal amide and glycine-alanine motifs, distinguishing it from known gut hormones. The complete purification and structural elucidation of galanin occurred in 1983, when Tatemoto and colleagues sequenced the 29-amino-acid from porcine intestine using following extensive HPLC fractionation. Early bioassays revealed galanin's potent contractile effects on and inhibitory actions on pancreatic exocrine and insulin release, confirming its biological relevance as a . These findings underscored galanin's role in peripheral regulation, prompting subsequent investigations into its distribution. The encoding galanin was cloned in 1987, marking a transition to molecular studies.

Gene and Protein Structure

Galanin is encoded by the GAL gene, located on the long arm of at position 11q13.2 (genomic coordinates 68,684,544–68,691,175 on GRCh38.p14). The gene spans approximately 6.6 kb and consists of six exons, producing a transcript (NM_015973.5) that translates into a 123-amino-acid precursor protein known as preprogalanin. This precursor includes a 19-amino-acid (residues 1–19), the mature galanin sequence (residues 20–49), and a 60-amino-acid galanin message-associated (GMAP, residues 64–123) with potential properties. The first cDNA clones for galanin were isolated in 1987 from pituitary tumor mRNA, revealing the precursor structure and enabling subsequent sequencing efforts. The mature galanin in humans comprises 30 (: GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS), with a molecular formula of C139H210N42O43 and a of 3,157.4 g/mol. In most other mammals, including rats, mice, pigs, and cows, the mature is 29 long due to the absence of the C-terminal serine residue. The is generated through proteolytic processing of preprogalanin, involving endoproteolytic cleavage at dibasic sites (e.g., by convertases) followed by carboxypeptidase removal of basic residues. Key post-translational modifications include C-terminal α-amidation, essential for , mediated by peptidylglycine α-amidating monooxygenase, and potential N-terminal in some contexts. Galanin exhibits high sequence conservation across mammals, with greater than 85% overall homology between human, rat, mouse, porcine, and bovine orthologs. The N-terminal 15 residues (GWTLNSAGYLLGPHA) are identical across these species, reflecting their critical role in structural stability, while the C-terminal region displays greater variability, contributing to species-specific functional nuances. For instance, the human-specific extension at the C-terminus may influence processing efficiency or peptide stability compared to the shorter forms in rodents and other mammals. Such variations underscore the evolutionary conservation of core neuromodulatory functions alongside adaptations in peripheral tissues.

Receptors and Signaling

Receptor Subtypes

Galanin exerts its effects through three distinct subtypes, GALR1, GALR2, and GALR3, all of which possess seven transmembrane domains characteristic of class A GPCRs. These receptors share low (approximately 35-40% identity) but are highly conserved across mammals, enabling galanin binding and subsequent . GALR1 and GALR3 primarily couple to Gi/o proteins, leading to inhibitory signaling via suppression, while GALR2 couples to both Gq/11 (activating and excitatory pathways) and Gi/o (inhibitory), allowing for dual functional outcomes. GALR3 remains the least characterized subtype in terms of downstream effects and . The human GALR1 gene is located on chromosome 18q23, spanning four exons and encoding a 349-amino-acid protein. It exhibits high expression in central nervous system regions such as the hypothalamus, hippocampus, amygdala, cortex, basal forebrain, and spinal cord, with lower levels in peripheral tissues like the gastrointestinal tract. The GALR2 gene resides on chromosome 17q25.1, also comprising four exons and producing a 387-amino-acid protein; its expression is broader, including central sites like the hypothalamus and peripheral organs such as the pituitary gland, heart, kidney, liver, pancreas, and gastrointestinal tract. In contrast, the GALR3 gene on chromosome 22q13.1 has two exons and encodes a 368-amino-acid protein, predominantly expressed in peripheral tissues including the kidney, lung, adrenal gland, and placenta, with minimal presence in the brain. All three receptors bind galanin with nanomolar affinity, though GALR1 and GALR2 display higher potency (Ki ≈ 0.1-1 nM) compared to GALR3 (Ki ≈ 1-10 nM). Recent cryo-electron microscopy studies have provided structural insights into recognition, revealing conserved binding pockets involving extracellular loops and transmembrane helices, with galanin engaging key residues like Arg146 in GALR1 for selectivity. A 2025 study highlighted cholesterol's role in modulating GALR1 trafficking and lateral mobility in live cells, where depletion reduces receptor surface expression and binding, whereas GALR2 function remains unaffected, underscoring subtype-specific lipid dependencies. To monitor galanin-GALR1 interactions dynamically, NanoBRET assays using HiBiT-tagged peptide s have been developed, enabling real-time quantification of binding and internalization in living cells with high sensitivity and minimal perturbation. These assays confirm galanin's rapid engagement of GALR1, facilitating studies on selectivity and receptor dynamics without radioactive labels.

Signaling Pathways

Galanin receptors, as G-protein-coupled receptors, initiate diverse intracellular signaling cascades upon ligand binding. GALR1 and GALR3 primarily couple to Gi/o proteins, leading to the inhibition of adenylyl cyclase and a subsequent decrease in cyclic AMP (cAMP) levels. This reduction in cAMP modulates downstream effectors such as protein kinase A (PKA), influencing cellular excitability and gene expression. Additionally, activation of GALR1 and GALR3 stimulates G-protein-gated inwardly rectifying potassium (GIRK) channels, promoting membrane hyperpolarization and neuronal inhibition. In contrast, GALR2 couples predominantly to Gq/11 proteins, activating (PLC) and hydrolyzing (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of Ca²⁺ from intracellular stores, while DAG activates (PKC), initiating a cascade of events that enhance cellular responsiveness. GALR2 signaling also engages the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, which regulates proliferation, differentiation, and survival signals. Galanin receptor signaling exhibits crosstalk with other neurotransmitter systems, notably modulating the release of acetylcholine (ACh) and serotonin (5-HT). For instance, galanin inhibits ACh release in the basal forebrain and hippocampus via GALR1, altering cholinergic transmission. Similarly, it suppresses 5-HT release in the ventral hippocampus through interactions at GALR1 and GALR3, potentially via Gi/o-mediated inhibition of presynaptic calcium influx. Following peripheral , galanin receptor signaling undergoes adaptive changes, including upregulation of GALR1 and GALR2 expression in sensory neurons and the . This enhances galanin-mediated inhibition of nociceptive transmission and promotes through amplified Gi/o and Gq pathways. Recent studies have elucidated GALR1's role in hippocampal-prefrontal cortical circuits, where its activation in ventral prefrontal cortex (vPFC) neurons modulates cognitive control processes such as and impulse via Gi/o-coupled inhibition.

Expression and Distribution

Tissue Distribution

Galanin, a 30-amino-acid , exhibits widespread expression across the central and peripheral nervous systems, with particularly high levels observed in the (CNS), including the and , as well as in the gastrointestinal () tract, notably the . In the CNS, galanin immunoreactivity is prominent in noradrenergic neurons of the and various hypothalamic nuclei, where it co-localizes with classical neurotransmitters. Within the GI tract, galanin concentrations peak in the , decreasing progressively toward the stomach and more distal intestinal segments, primarily localizing to enteric neurons. In peripheral tissues, galanin is expressed in the skin, where it is found in , fibroblasts, and endings; , particularly in cells; and the adrenal glands, including medullary chromaffin cells. Galanin often co-expresses with other neuropeptides in sensory neurons, such as (CGRP) and vasoactive intestinal polypeptide (VIP) in dorsal root ganglia (DRG), contributing to its role in circuits. Expression patterns of galanin exhibit species-specific variations; for instance, galanin co-expression with serotonin systems in the differs between and , and its abundance in the is more pronounced in humans compared to some . Developmental changes also occur, with galanin emerging early in sensory ganglia (e.g., trigeminal and DRG) around embryonic day 14 in rats, and transient upregulation in thalamic neurons during whisker map formation in infant mice. A recent mapping study in 2025 identified a specific of galanin-positive neurons in the lumbar spinal cord of male mice, localized to the L3-L4 segments and integrated into circuits modulating .

Regulation of Expression

Galanin is dynamically regulated by various physiological and pathological stimuli, primarily through transcriptional mechanisms involving specific promoter and enhancer regions. The GAL gene promoter contains response elements that mediate activation in response to second messenger pathways, such as those triggered by phorbol esters and , enabling tissue-specific control. An enhancer region upstream of the GAL gene directs expression to dorsal root ganglia and confers responsiveness to axotomy, highlighting its role in injury-induced upregulation. Additionally, estrogen response elements within the GAL gene promoter bind receptors, facilitating hormonal regulation of transcription. Nerve injury potently upregulates galanin expression, particularly in sensory neurons, where levels can increase up to 120-fold following peripheral axotomy. In the , chronic infusion induces a 3- to 4-fold elevation in galanin mRNA within neurons, supporting its adaptive role post-injury. similarly enhances galanin expression both centrally and peripherally, with neuronal and non-neuronal sources contributing to the response in models of acute inflammation. Hormonal factors, such as , further drive upregulation; rapidly induces GAL mRNA in the and via direct promoter interactions. During development, galanin expression is tightly regulated in derivatives, appearing transiently in migratory cells of the sympathetic chain, nodose ganglion, and mesenchymal tissues around embryonic day 10 in mice. This pattern suggests galanin supports proliferation and migration before target innervation, with expression linked to transcription factors like Foxa2 in early endodermal and contexts. In pathological settings, such as lesions, galanin upregulation persists, modulating effects in hippocampal circuits. Recent research in 2025 using models of demonstrates galanin-mediated regulation of inflammation during regeneration. Following transection, galanin expression peaks at 4 hours post-lesion, promoting migration and upregulation of pro- and genes (e.g., il1b, tnfα, il10, mmp9), which are suppressed in galanin knockouts, delaying axonal regrowth and functional recovery.

Physiological Functions

Central Nervous System Roles

Galanin modulates neuronal excitability in the primarily through inhibitory effects on release, including (ACh) and serotonin (5-HT). In the hippocampus, of galanin inhibits ACh release, contributing to deficits in learning and processes. Similarly, intracerebroventricular galanin administration produces a dose-dependent inhibition of 5-HT release in the ventral hippocampus, lasting over and mediated by galanin receptor subtype 1 (GalR1), which hyperpolarizes serotonergic neurons. Galanin also suppresses glutamate release in the arcuate nucleus of the by acting presynaptically to reduce excitatory postsynaptic currents by approximately 55%, without postsynaptic effects or involvement of K⁺ channels. In sleep regulation, galanin plays a key role in following increased neuronal activity, as demonstrated in models. Galanin-expressing neurons in the activate during recovery sleep, with expression increasing 3- to 4-fold after pharmacological or heightened activity induced by agents like (PTZ). Galanin mutants exhibit nearly complete abolition of rebound sleep, underscoring its necessity for homeostasis. A 2025 study in further highlights galanin's sedative effects, where overexpression reduces overall brain activity and large calcium event frequency, promoting rest after stress, though acute stress can compromise this regulation. Galanin influences cognitive functions, particularly weakening learning and memory via GalR1-mediated circuits in the hippocampus and . Pharmacological stimulation of GalR1 in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) disrupts and increases impulsive errors in goal-directed tasks, with vPFC GalR1 neurons predicting correct responses and vHC activity correlating with processing. These effects, observed in rat models using and photometry, indicate distinct roles for vPFC GalR1 neurons in cognitive control and vHC neurons in error monitoring. Behaviorally, galanin neurons in the medial preoptic area (MPOA) govern parental responses and suppress in mice. Activation of MPOA galanin neurons during parenting inhibits pup-directed in virgin males, inducing nurturing behaviors like grooming, while genetic ablation impairs in both sexes and increases . Galanin also modulates mood by enhancing noradrenaline and serotonin release in the hippocampus under stress, as seen in galanin-overexpressing mice where repeated forced swimming elevates these neurotransmitters by 275% and 344%, respectively, effects blocked by galanin antagonists. In , galanin exhibits properties by increasing thresholds through analogs like NAX 5055. This systemically active GalR1-preferring analog provides full protection against in models of partial and pharmacoresistant , including corneal kindling and 6 Hz psychomotor , without activity in maximal electroshock models. Overall, galanin maintains excitability with multifaceted inhibitory actions, reducing neuronal activity under normal conditions and during via GalR1a, though it may paradoxically increase occurrence under acute stress in . This bidirectional regulation supports galanin's role in balancing , stress responses, and .

Peripheral and Endocrine Roles

Galanin exerts significant inhibitory effects on gastrointestinal motility, acting primarily through the to modulate contraction and . In the and , it delays gastric emptying and reduces the amplitude of contractile waves, as demonstrated in studies where intravenous galanin administration significantly prolonged the time for 50% gastric emptying compared to controls. Furthermore, galanin suppresses the release of gut hormones such as (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) via activation of GAL1 receptors on enteroendocrine cells, thereby fine-tuning postprandial responses. These actions occur through galanin-expressing neurons in the myenteric and submucosal plexuses, where it co-localizes with other inhibitory peptides like vasoactive intestinal polypeptide (VIP). In the endocrine system, galanin plays a key regulatory role in pancreatic secretion and . It potently inhibits glucose-stimulated insulin and release from pancreatic beta and delta cells, respectively, while stimulating secretion from alpha cells, effects mediated primarily by GAL1 and GAL2 receptors. This dual modulation contributes to galanin's involvement in systemic glucose metabolism; for instance, enteric administration of galanin in diabetic models enhances release from nNOS-expressing neurons, reducing duodenal glucose absorption and improving peripheral tissue uptake via hypothalamic signaling and AMPK activation in muscle. Additionally, galanin participates in release from lactotrophs, potentially influencing reproductive and metabolic axes. Galanin is co-localized with and in a subset of small-diameter sensory neurons within dorsal root ganglia (DRG), where it modulates nociceptive signaling. Under physiological conditions, baseline expression supports sensory transduction, but its role becomes prominent in injury contexts, where galanin upregulation in DRG neurons—up to 120-fold after axotomy—shifts toward antinociception via GAL1 receptor activation, reducing thermal and mechanical hypersensitivity. This peripheral modulation occurs independently of central inputs, highlighting galanin's local influence on primary afferent processing. In the , galanin-positive in the lumbar spinal cord (segments L2/L3) form a critical circuit for male sexual function, providing monosynaptic input to motor neurons innervating the in L6/S1. These neurons integrate genital sensory signals and drive rhythmic contractions essential for ; optogenetic stimulation evokes bulbospongiosus activity mimicking the expulsion phase, while genetic prolongs latency and disrupts copulatory patterns in mice. This spinal mechanism operates autonomously but is gated by descending inputs, underscoring galanin's peripheral coordination of reproductive reflexes. Recent neuronal studies reveal galanin's prominent co-expression in noradrenergic neurons of the , where it is detected in nearly all tyrosine hydroxylase-positive cells and modulates excitability via autocrine GAL1 receptor signaling. Activation of these receptors hyperpolarizes neurons through opening, reducing firing rates and influencing peripheral noradrenergic outflow to visceral targets. This diversity in noradrenergic populations highlights galanin's role in autonomic regulation beyond central circuits.

Clinical Significance

Metabolic and Behavioral Disorders

Galanin plays a significant role in the regulation of and energy balance, primarily through its actions in the . Central administration of galanin in stimulates food intake, particularly of high-fat diets, by acting on galanin receptors in key hypothalamic nuclei such as the paraventricular nucleus (PVN) and arcuate nucleus. This orexigenic effect contributes to the maintenance of , where galanin counteracts signals and promotes feeding behaviors essential for survival under conditions of energy deficit. Dysregulation of hypothalamic galanin signaling has been implicated in hyperphagia observed in models of , such as Zucker rats, highlighting its influence on overall metabolic control. In metabolic disorders, galanin exhibits complex associations with , , and mellitus (T2DM). While galanin itself promotes feeding, its interaction with related neuropeptides like spexin modulates energy expenditure and glucose metabolism; a 2023 review underscores how imbalances in the galanin-spexin axis may exacerbate and contribute to obesity-driven T2DM . Recent findings from 2025 further link elevated galanin-galanin receptor 1 (GAL-GALR1) signaling to alongside markers like and in patients with , correlating with metabolic perturbations that worsen affective symptoms and chronic fatigue syndrome. These associations suggest galanin's broader involvement in peripheral metabolic dysregulation, though its precise mechanistic contributions to T2DM progression remain under investigation. Galanin modulates addictive behaviors by influencing reward pathways, particularly through interactions with the mesolimbic system. In animal models, galanin attenuates alcohol consumption and preference, while also reducing self-administration and reward sensitivity, effects mediated by galanin receptors in the and . Genetic studies in humans support these findings, indicating galanin polymorphisms as risk factors for involving alcohol, , and . Regarding behavioral disorders, galanin exerts receptor-specific effects on depression and stress-related behaviors. Activation of galanin receptors, particularly GALR2, produces antidepressant-like effects in models of depression, reducing immobility in forced swim tests and enhancing resilience to . Conversely, GALR1 signaling may exacerbate anxiety-like behaviors under certain conditions, illustrating the nuanced, subtype-dependent modulation of mood and stress responses. These findings position galanin as a potential and therapeutic target in depression, with clinical antidepressants observed to alter galanin expression in preclinical studies.

Neurological and Neurodegenerative Diseases

Galanin expression is markedly upregulated in the of patients with (AD), where galanin-containing fibers hyperinnervate surviving neurons as a potential response to cholinergic degeneration. This hyperinnervation is thought to modulate function, but its role remains debated: while galanin inhibits release, potentially exacerbating cognitive deficits, it may also exert neuroprotective effects by preserving associated with neuronal survival in the basal forebrain. Studies in transgenic mice overexpressing galanin demonstrate impaired learning and in normal conditions, consistent with galanin's inhibitory actions on synaptic transmission, yet in AD models, elevated galanin levels might serve a compensatory function by enhancing resilience against degeneration. In , galanin exhibits properties primarily through inhibition of excitatory in the hippocampus, where it reduces glutamate release and susceptibility via activation of galanin receptors. Endogenous galanin depletion during exacerbates hippocampal , whereas administration of galanin or its agonists attenuates severity in rodent models, highlighting its role as an endogenous . During neural development, galanin regulates the survival and growth of (DRG) neurons; targeted disruption of the galanin gene results in a significant reduction in DRG neuron numbers, while exogenous galanin stimulates neurite outgrowth by modulating Rho and cofilin activity in sensory neurons. Recent findings from 2025 indicate that galanin facilitates spinal cord regeneration in by modulating post-injury inflammatory responses, promoting recovery after through regulation of immune cell dynamics and .

Pain, Epilepsy, and Neuroprotection

Galanin modulates transmission in a dose-dependent manner within the , primarily through its receptors GALR1 and GALR2. Activation of GALR1 at low concentrations facilitates , whereas higher concentrations engaging GALR2 exert anti-nociceptive effects by inhibiting primary afferent activity and reducing input to dorsal horn neurons. This biphasic action includes suppression of C-fiber evoked responses, as evidenced by reduced sensitization to C-fiber stimulation in galanin-overexpressing mice. In models of , exogenous galanin application alleviates hypersensitivity and promotes nerve regeneration, highlighting its therapeutic potential in peripheral . In epilepsy, galanin elevates the seizure threshold and attenuates kindling epileptogenesis through hippocampal mechanisms involving GALR1 and GALR2. Overexpression of galanin in transgenic models retards seizure generalization during hippocampal kindling, a standard model for temporal lobe epilepsy. Receptor subtype-selective agonists confirm that both GALR1 and GALR2 contribute to this anticonvulsant effect by modulating G-protein signaling cascades that dampen hyperexcitability. Galanin provides by promoting and neuronal survival following , with recent studies emphasizing its role in post-traumatic recovery. GALR2 is particularly linked to enhanced neurite outgrowth and regeneration in damaged sciatic nerves, as shown in models where galanin treatment accelerated functional recovery. A 2024 review underscores galanin's trophic effects in alleviating and supporting axonal regrowth after peripheral lesions. These protective actions involve receptor-specific inhibition of ; for instance, GALR2 predominates in shielding hippocampal neurons from glutamate-induced damage, while GALR1 deletion exacerbates vulnerability to kainate-mediated .

Emerging Therapeutic and Diagnostic Applications

Galanin receptor 2 (GALR2) agonists have shown promise as therapeutic agents for managing and providing . A review highlights the potential of peripherally acting GALR2 agonists to treat early-phase inflammatory by modulating nociceptive signaling in peripheral tissues, based on preclinical models demonstrating reduced behaviors without central side effects. Additionally, intranasal administration of GALR2 agonists in the ventral hippocampus has been linked to enhanced and long-term effects in models, suggesting neuroprotective applications in mood and cognitive disorders. Co-targeting galanin and spexin, a related , represents an emerging strategy for and mellitus (T2DM). A 2023 update indicates that both peptides influence through shared galanin receptors, with spexin agonists potentially counteracting galanin's orexigenic effects to promote and improve glycemic control in obesity-driven T2DM models. In the realm of anticonvulsants, analogs like NAX 5055, a metabolically stable galanin derivative, exhibit potent antiseizure activity. Preclinical studies in epilepsy models, including the 6 Hz psychomotor test, demonstrate that systemic administration of NAX 5055 suppresses refractory seizures by mimicking galanin's inhibitory effects on neuronal excitability, positioning it as a candidate for patients unresponsive to standard antiepileptic drugs. For diagnostics, galanin levels serve as a predictive in endometrial conditions and . A 2025 prospective study found elevated serum galanin in patients with endometrial atypical and compared to benign cases, correlating with increased —a key driver of endometrial —and enabling differentiation with high diagnostic accuracy. Emerging applications also extend to chronic conditions and tools. Increased galanin-GALR1 signaling has been associated with chronic fatigue syndrome symptoms in patients, alongside and , suggesting galanin modulation as a target for alleviating persistent fatigue and related neuropsychiatric effects. Potential roles in sleep disorders and are under investigation through 2025 spinal cord studies, where galanin dysregulation in spinal pathways may contribute to these comorbidities in states. For drug screening, the HiBiT-based NanoBRET enables real-time monitoring of binding to GALR1 in live cells, facilitating high-throughput evaluation of galanin receptor modulators for therapeutic development.

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