Galanin peptides (GAL) encodes a 123-amino-acid preproprotein cleaved into the mature 30-amino-acid non-amidated human neuropeptide galanin (residues 33-62) and the 59-amino-acid galanin message-associated peptide (GMAP, residues 65-123). Synthesized in central and peripheral neurons as well as neuroendocrine and epidermal cells, mature galanin is stored in dense-core secretory granules and released into the extracellular space, where its conserved N-terminal pharmacophore (Gly1-Trp2-Thr3-Leu4-Asn5-Ser6-Ala7-Gly8-Tyr9-Leu10-Leu11-Gly12-Pro13) binds and activates all three class A G-protein-coupled galanin receptors: GALR1 (Gi/o-coupled), GALR2 (Gq/11- and Gi/o-coupled), and GALR3 (Gi/o-coupled). Through galanin-activated receptor signaling, GAL modulates synaptic transmission, nociception, epileptiform excitability, neuroendocrine hormone secretion (including inhibition of glucose-stimulated insulin secretion and stimulation of adrenocortical cortisol release), and hair follicle cycling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004966 galanin receptor activity | IMP PMID:25691535 Galanin pathogenic mutations in temporal lobe epilepsy. | MODIFY | Summary: Ligand-receptor role conflation: GAL encodes the secreted neuropeptide hormone ligand, not the transmembrane galanin receptor. Reason: PMID:25691535 characterized a pathogenic temporal lobe epilepsy mutation (p.A39E) in the mature galanin peptide that alters its agonist/antagonist activity at GALR1 and GALR2. GAL is the extracellular peptide ligand (GO:0005184 neuropeptide hormone activity, GO:0031764 type 1 galanin receptor binding, GO:0031765 type 2 galanin receptor binding), not the receptor. Proposed replacements: neuropeptide hormone activity type 1 galanin receptor binding type 2 galanin receptor binding Supporting Evidence: PMID:25691535 Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. |
| GO:0005179 hormone activity | IEA GO_REF:0000002 | MODIFY | Summary: Broad hormone activity annotation that should be refined to neuropeptide hormone activity. Reason: GO:0005179 (hormone activity) is true of galanin but less specific than GO:0005184 (neuropeptide hormone activity), which is already directly supported by experimental and phylogenetic evidence on this gene (PMID:24517231, PMID:1722333). Proposed replacements: neuropeptide hormone activity |
| GO:0005184 neuropeptide hormone activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature human galanin as a secreted neuropeptide hormone. Reason: Mature human galanin (30 residues) is a canonical neuropeptide hormone secreted by central and peripheral neurons and neuroendocrine cells to activate GALR1, GALR2, and GALR3 and inhibit glucose-stimulated insulin secretion (PMID:1722333, PMID:1370155, PMID:25691535). Supporting Evidence: PMID:1722333 Compared to the 29-residue porcine, rat, and bovine Gals, hGal uniquely comprises 30 amino acids possessing an additional nonamidated serine residue as C terminus. PMID:1370155 Human galanin inhibited glucose-stimulated insulin secretion in a dose-dependent manner in RIN cells. Human, porcine, and rat galanin exhibited similar activity with ED50 less than 1 nM. |
| GO:0005184 neuropeptide hormone activity | IDA PMID:24517231 Coevolution of the spexin/galanin/kisspeptin family: Spexin ... | ACCEPT | Summary: Core molecular function of mature human galanin as a secreted neuropeptide hormone. Reason: Mature human galanin (30 residues) is a canonical neuropeptide hormone secreted by central and peripheral neurons and neuroendocrine cells to activate GALR1, GALR2, and GALR3 and inhibit glucose-stimulated insulin secretion (PMID:1722333, PMID:1370155, PMID:24517231). Supporting Evidence: PMID:1722333 Compared to the 29-residue porcine, rat, and bovine Gals, hGal uniquely comprises 30 amino acids possessing an additional nonamidated serine residue as C terminus. PMID:1370155 Human galanin inhibited glucose-stimulated insulin secretion in a dose-dependent manner in RIN cells. Human, porcine, and rat galanin exhibited similar activity with ED50 less than 1 nM. |
| GO:0005184 neuropeptide hormone activity | NAS PMID:1722333 Isolation and primary structure of pituitary human galanin, ... | ACCEPT | Summary: Core molecular function of mature human galanin as a secreted neuropeptide hormone. Reason: Mature human galanin (30 residues) is a canonical neuropeptide hormone secreted by central and peripheral neurons and neuroendocrine cells to activate GALR1, GALR2, and GALR3 and inhibit glucose-stimulated insulin secretion (PMID:1722333, PMID:1370155, PMID:25691535). Supporting Evidence: PMID:1722333 Compared to the 29-residue porcine, rat, and bovine Gals, hGal uniquely comprises 30 amino acids possessing an additional nonamidated serine residue as C terminus. PMID:1370155 Human galanin inhibited glucose-stimulated insulin secretion in a dose-dependent manner in RIN cells. Human, porcine, and rat galanin exhibited similar activity with ED50 less than 1 nM. |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | MODIFY | Summary: Generic protein binding row for GAL interaction with GALR2 (O43603) that should be refined to type 2 galanin receptor binding. Reason: Interaction of mature galanin with UniProtKB:O43603 (human GALR2) represents specific ligand binding to the type 2 galanin receptor (GO:0031765) (PMID:23597562, PMID:25691535). Proposed replacements: type 2 galanin receptor binding |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | MODIFY | Summary: Generic protein binding row for GAL interaction with GALR1 (P47211) that should be refined to type 1 galanin receptor binding. Reason: Interaction of mature galanin with UniProtKB:P47211 (human GALR1) represents specific ligand binding to the type 1 galanin receptor (GO:0031764) (PMID:23597562, PMID:25691535). Proposed replacements: type 1 galanin receptor binding |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:25416956) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:25691535 Galanin pathogenic mutations in temporal lobe epilepsy. | MODIFY | Summary: Generic protein binding row for GAL interaction with GALR2 (O43603) that should be refined to type 2 galanin receptor binding. Reason: Interaction of mature galanin with UniProtKB:O43603 (human GALR2) represents specific ligand binding to the type 2 galanin receptor (GO:0031765) (PMID:23597562, PMID:25691535). Proposed replacements: type 2 galanin receptor binding |
| GO:0005515 protein binding | IPI PMID:25691535 Galanin pathogenic mutations in temporal lobe epilepsy. | MODIFY | Summary: Generic protein binding row for GAL interaction with GALR1 (P47211) that should be refined to type 1 galanin receptor binding. Reason: Interaction of mature galanin with UniProtKB:P47211 (human GALR1) represents specific ligand binding to the type 1 galanin receptor (GO:0031764) (PMID:23597562, PMID:25691535). Proposed replacements: type 1 galanin receptor binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32296183) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32296183) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32296183) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32296183) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32814053) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32814053) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32814053) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Uninformative generic protein binding annotation from high-throughput interactome screening. Reason: Bare GO:0005515 (protein binding) from high-throughput yeast two-hybrid screening (PMID:32814053) carries no specific molecular function information and is removed per the protein-binding curation policy; removal does not imply the binary assay observation is false. |
| GO:0005576 extracellular region | EXP PMID:1370155 Sequence of human galanin and its inhibition of glucose-stim... | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | EXP PMID:1722333 Isolation and primary structure of pituitary human galanin, ... | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | IDA PMID:9402244 Concomitant evaluation of plasma galanin and catecholamine l... | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-389026 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Core extracellular localization of secreted mature galanin. Reason: Mature galanin is secreted into the extracellular space and circulation where it engages cell-surface galanin receptors (PMID:1722333, PMID:9402244, PMID:1370155). Supporting Evidence: PMID:9402244 The neuropeptide galanin (GAL) is localized in the peripheral and central nervous systems as well as in the adrenal medulla where it coexists with catecholamines. |
| GO:0007165 signal transduction | IDA PMID:24602615 Activation of galanin receptor 2 stimulates large conductanc... | MODIFY | Summary: Broad signal transduction annotation that should be refined to galanin-activated signaling pathway. Reason: GO:0007165 (signal transduction) is true but too general; PMID:24602615 specifically characterized galanin activation of GALR2 IP3/Ca2+ signaling, which is captured by GO:0090663 (galanin-activated signaling pathway). Proposed replacements: galanin-activated signaling pathway Supporting Evidence: PMID:24602615 Taken together, activation of GalR2 leads to elevation of intracellular Ca(2+) is due to Ca(2+) efflux from ER through IP3R sequentially opening BK channels. |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Tissue-specific adrenocortical adenylate cyclase/PKA-dependent GALR1 signaling branch stimulated by galanin. Reason: Although GALR1 and GALR3 canonically couple to Gi/o (inhibiting adenylate cyclase) in neurons and GALR2 couples to Gq/11 (PMID:24602615), PMID:17982695 directly demonstrated that 10 nM galanin enhances cAMP production and cortisol secretion in dispersed human inner adrenocortical cells via GALR1, and that this response is suppressed by the adenylate cyclase inhibitor SQ-22536 and the PKA inhibitor H-89. Kept as non-core for this tissue-restricted adrenocortical signaling branch. Supporting Evidence: PMID:17982695 Galanin (10(-8) M) and ACTH (10(-9) M) enhanced cyclic-AMP production from dispersed cells, and the response was suppressed by the adenylate cyclase inhibitor SQ-22536 (10(-4) M). |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:17982695 Galanin stimulates cortisol secretion from human adrenocorti... | KEEP AS NON CORE | Summary: Tissue-specific adrenocortical adenylate cyclase/PKA-dependent GALR1 signaling branch stimulated by galanin. Reason: Although GALR1 and GALR3 canonically couple to Gi/o (inhibiting adenylate cyclase) in neurons and GALR2 couples to Gq/11 (PMID:24602615), PMID:17982695 directly demonstrated that 10 nM galanin enhances cAMP production and cortisol secretion in dispersed human inner adrenocortical cells via GALR1, and that this response is suppressed by the adenylate cyclase inhibitor SQ-22536 and the PKA inhibitor H-89. Kept as non-core for this tissue-restricted adrenocortical signaling branch. Supporting Evidence: PMID:17982695 Galanin (10(-8) M) and ACTH (10(-9) M) enhanced cyclic-AMP production from dispersed cells, and the response was suppressed by the adenylate cyclase inhibitor SQ-22536 (10(-4) M). |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process of mature galanin in initiating neuropeptide receptor signaling. Reason: Galanin is a classical neuropeptide that signals through GPCRs (GALR1-3) in the central and peripheral nervous systems (PMID:25691535, PMID:24602615). Supporting Evidence: PMID:25691535 Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. |
| GO:0007626 locomotory behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream central nervous system behavioral effect of galanin signaling on locomotion. Reason: Central galanin receptor activation modulates striatal and spinal motor circuits to influence locomotory activity in rodents; kept as a non-core organismal behavioral readout downstream of galanin neuropeptide signaling. |
| GO:0007631 feeding behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream hypothalamic orexigenic role of galanin signaling in feeding behavior. Reason: Hypothalamic galanin release acts on arcuate and paraventricular galanin receptors to stimulate food intake; kept as a non-core physiological readout downstream of neuropeptide receptor activation. |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream antiproliferative effect of galanin signaling in target tissues such as hair follicle keratinocytes and pituitary cells. Reason: Galanin signaling inhibits proliferation of human hair matrix keratinocytes in situ (PMID:22329353) and neuroendocrine target cells in rodents; kept as a non-core cellular outcome of receptor activation. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation (response to xenobiotic stimulus) transferred from rodent studies where Gal mRNA or peptide levels change after xenobiotic exposure. Reason: Orthology transfer from rat Gal reflects transcriptional or peptide-level changes following xenobiotic administration rather than galanin directly executing a xenobiotic detoxification or response pathway. |
| GO:0030073 insulin secretion | NAS PMID:1370155 Sequence of human galanin and its inhibition of glucose-stim... | MODIFY | Summary: Imprecise insulin secretion annotation where experimental evidence demonstrates negative regulation of glucose-stimulated insulin secretion. Reason: PMID:1370155 demonstrated that synthetic human galanin (1-30) dose-dependently inhibits glucose-stimulated insulin secretion from pancreatic beta-like RIN m5F cells; GO:0046676 (negative regulation of insulin secretion) captures the correct regulatory sign. Proposed replacements: negative regulation of insulin secretion Supporting Evidence: PMID:1370155 Human galanin inhibited glucose-stimulated insulin secretion in a dose-dependent manner in RIN cells. Human, porcine, and rat galanin exhibited similar activity with ED50 less than 1 nM. |
| GO:0030141 secretory granule | IBA GO_REF:0000033 | ACCEPT | Summary: Core subcellular storage compartment of processed galanin prior to regulated exocytosis. Reason: Like other neuropeptide precursors, progalanin is packaged and processed in dense-core secretory granules of neurons and neuroendocrine cells prior to release. |
| GO:0030141 secretory granule | IEA GO_REF:0000107 | ACCEPT | Summary: Core subcellular storage compartment of processed galanin prior to regulated exocytosis. Reason: Like other neuropeptide precursors, progalanin is packaged and processed in dense-core secretory granules of neurons and neuroendocrine cells prior to release. |
| GO:0031764 type 1 galanin receptor binding | IDA PMID:24517231 Coevolution of the spexin/galanin/kisspeptin family: Spexin ... | ACCEPT | Summary: Core molecular function of mature galanin as a high-affinity agonist ligand for GALR1. Reason: Human galanin directly binds and activates human type 1 galanin receptor (GALR1) with sub-nanomolar potency, whereas spexin does not activate GALR1 (PMID:24517231, PMID:25691535, PMID:17982695). Supporting Evidence: PMID:25691535 Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. PMID:17982695 We conclude that galanin stimulates cortisol secretion from human inner adrenocortical cells, acting through GAL-R1 coupled to the adenylate cyclase/PKA-dependent signaling cascade via a Ptx-sensitive Galpha protein. |
| GO:0031765 type 2 galanin receptor binding | IDA PMID:24517231 Coevolution of the spexin/galanin/kisspeptin family: Spexin ... | ACCEPT | Summary: Core molecular function of mature galanin as a high-affinity agonist ligand for GALR2. Reason: Human galanin directly binds and activates human type 2 galanin receptor (GALR2) with nanomolar potency (PMID:25691535, PMID:24602615, PMID:24517231). Supporting Evidence: PMID:25691535 Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. PMID:24602615 This activation was mediated by GalR2, since its agonist AR-M1896 mimicked the effect of galanin, and since galanin did not facilitate BK currents in cells co-expressing cDNAs of BK and GalR1 or GalR3. |
| GO:0031766 type 3 galanin receptor binding | IDA PMID:24517231 Coevolution of the spexin/galanin/kisspeptin family: Spexin ... | ACCEPT | Summary: Core molecular function of mature galanin as an agonist ligand for GALR3. Reason: PMID:24517231 directly compared human galanin (GAL) and spexin (SPX) potency across human GALR1, GALR2, and GALR3, showing that GAL binds and activates human GALR3 (albeit with lower potency than SPX). Supporting Evidence: PMID:24517231 A ligand-receptor interaction study showed that SPXs activate human, Xenopus, and zebrafish GALR2/3 family receptors but not GALR1, suggesting that SPXs are natural ligands for GALR2/3. Particularly, SPXs exhibited much higher potency toward GALR3 than GAL. |
| GO:0031943 regulation of glucocorticoid metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream adrenocortical steroidogenic effect of galanin signaling on glucocorticoid metabolism. Reason: Galanin stimulates glucocorticoid (cortisol/corticosterone) secretion from adrenocortical cells via GALR1 (PMID:17982695); kept as a non-core endocrine effector outcome downstream of galanin receptor activation. |
| GO:0032868 response to insulin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation (response to insulin) transferred from rodent studies where Gal mRNA or peptide levels change after insulin administration. Reason: Orthology transfer from rat Gal reflects changes in hypothalamic or peripheral Gal expression following insulin administration rather than galanin directly mediating the intracellular insulin signaling pathway. |
| GO:0035902 response to immobilization stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation (response to immobilization stress) transferred from rodent studies where Gal mRNA or peptide levels are induced by restraint stress. Reason: Orthology transfer from rat Gal reflects stress-induced transcriptional upregulation of Gal in central noradrenergic and hypothalamic neurons during immobilization stress rather than a core molecular function of galanin. |
| GO:0042756 drinking behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream hypothalamic behavioral effect of central galanin signaling on water intake. Reason: Central galanin administration modulates dipsogenic circuits in the hypothalamus in rodents; kept as a non-core organismal behavioral readout downstream of galanin receptor signaling. |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | ACCEPT | Summary: Valid neuronal subcellular localization where galanin is synthesized and stored in human diencephalic neurons. Reason: Immunohistochemistry in the human diencephalon directly demonstrates galanin immunoreactivity in neuronal cell bodies (PMID:23415787). Supporting Evidence: PMID:23415787 Our studies show that among the three catecholamines, dopamine is the most abundant and the vast majority of catecholaminergic contacts on galanin-immunoreactive neurons is dopaminergic. |
| GO:0043025 neuronal cell body | IDA PMID:23415787 Catecholaminergic system innervates galanin-immunoreactive n... | ACCEPT | Summary: Valid neuronal subcellular localization where galanin is synthesized and stored in human diencephalic neurons. Reason: Immunohistochemistry in the human diencephalon directly demonstrates galanin immunoreactivity in neuronal cell bodies (PMID:23415787). Supporting Evidence: PMID:23415787 Our studies show that among the three catecholamines, dopamine is the most abundant and the vast majority of catecholaminergic contacts on galanin-immunoreactive neurons is dopaminergic. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream pro-apoptotic effect of GALR2 signaling in specific neuroendocrine and epithelial cell types. Reason: Galanin signaling through GALR2 can promote apoptosis in pituitary lactotrophs and specific carcinoma lines; kept as a non-core cellular outcome downstream of receptor activation. |
| GO:0043627 response to estrogen | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation (response to estrogen) transferred from rodent studies where pituitary Gal transcription is strongly induced by estradiol. Reason: Orthology transfer from rat Gal reflects estrogen-receptor-driven transcriptional induction of the Gal gene in anterior pituitary lactotrophs rather than galanin mediating estrogen signaling. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24517231 Coevolution of the spexin/galanin/kisspeptin family: Spexin ... | MODIFY | Summary: Assay readout over-annotation from an SRE-luciferase reporter assay used to measure GALR1/GALR2/GALR3 activation. Reason: PMID:24517231 used serum-response-element (SRE)-luciferase reporter transcription as a heterologous GPCR signaling readout in HEK293 cells; galanin's biological role in that assay is initiating the galanin-activated signaling pathway (GO:0090663), not directly regulating RNA polymerase II transcription. Proposed replacements: galanin-activated signaling pathway |
| GO:0048149 behavioral response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream central nervous system neuromodulatory effect of galanin on ethanol intake and reward behavior. Reason: Hypothalamic and mesolimbic galanin signaling modulates voluntary ethanol consumption and behavioral responses to ethanol in rodents; kept as a non-core organismal behavioral phenotype. |
| GO:0050672 negative regulation of lymphocyte proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream immunomodulatory effect of galanin signaling on lymphocyte proliferation. Reason: Exogenous galanin attenuates mitogen-stimulated lymphocyte proliferation in rodent lymphoid assays; kept as a non-core paracrine immunomodulatory readout. |
| GO:0051464 positive regulation of cortisol secretion | IDA PMID:17982695 Galanin stimulates cortisol secretion from human adrenocorti... | KEEP AS NON CORE | Summary: Tissue-specific steroidogenic effect of galanin stimulating cortisol release from human inner adrenocortical cells. Reason: PMID:17982695 demonstrated that galanin stimulates cortisol secretion from dispersed human inner adrenocortical cells via GALR1 and cAMP/PKA signaling; kept as a non-core tissue-restricted endocrine outcome downstream of GALR1 activation. Supporting Evidence: PMID:17982695 We conclude that galanin stimulates cortisol secretion from human inner adrenocortical cells, acting through GAL-R1 coupled to the adenylate cyclase/PKA-dependent signaling cascade via a Ptx-sensitive Galpha protein. |
| GO:0051795 positive regulation of timing of catagen | IDA PMID:22329353 The neuropeptide galanin is a novel inhibitor of human hair ... | KEEP AS NON CORE | Summary: Tissue-specific paracrine role of galanin in promoting premature catagen entry in human hair follicles. Reason: PMID:22329353 showed that galanin inhibits hair matrix keratinocyte proliferation and accelerates transition from anagen to catagen in organ-cultured human hair follicles; kept as a non-core tissue-specific developmental/physiological effect. Supporting Evidence: PMID:22329353 Galanin reduced proliferation of hair matrix keratinocytes in situ compared with vehicle-treated controls, shortened the hair growth phase (anagen) in vitro and reduced hair shaft elongation. |
| GO:1901652 response to peptide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation (response to peptide) transferred from rodent studies where Gal mRNA or secretion changes following peptide hormone challenge. Reason: Orthology transfer from rat Gal reflects changes in Gal mRNA or peptide release after exogenous peptide hormone stimulation rather than galanin directly executing a cellular response-to-peptide pathway. |
| GO:0090663 galanin-activated signaling pathway | IC PMID:25691535 Galanin pathogenic mutations in temporal lobe epilepsy. | NEW | Summary: Mature human galanin directly initiates the galanin-activated signaling pathway by binding and activating GALR1, GALR2, and GALR3. Reason: Mature human galanin is the defining endogenous peptide agonist for all three human galanin receptors (GALR1, GALR2, and GALR3), directly triggering Gi/o- and Gq/11-coupled intracellular signaling cascades (PMID:25691535, PMID:24602615, PMID:24517231). Inferred from GO:0031764 (type 1 galanin receptor binding), GO:0031765 (type 2 galanin receptor binding), and GO:0031766 (type 3 galanin receptor binding). Supporting Evidence: PMID:25691535 Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. PMID:24602615 Taken together, activation of GalR2 leads to elevation of intracellular Ca(2+) is due to Ca(2+) efflux from ER through IP3R sequentially opening BK channels. |
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Download this section (compressed HTML)Q: Does the 59-amino-acid galanin message-associated peptide (GMAP) cleaved from human preprogalanin engage a dedicated cell-surface receptor in human tissues, or is its biological activity restricted to antimicrobial defense?
Suggested experts: Tomas Hokfelt, Barbara Kofler, Jae Young Seong
Experiment: Determine cryo-EM structures and perform molecular dynamics simulations of wild-type vs. Ala7Glu human galanin(1-30) bound to GALR1-Gi and GALR2-Gq complexes.
Hypothesis: The temporal lobe epilepsy mutation p.A39E (Ala7Glu in mature human galanin) destabilizes the N-terminal alpha-helical conformation within the extracellular vestibule of GALR1 and GALR2, converting a full agonist into a receptor antagonist.
Type: Cryo-electron microscopy and G-protein BRET signaling assay
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