id: MODULE:galanin_signaling title: Galanin-activated signaling pathway module description: >- The galanin-activated signaling pathway (GO:0090663) is initiated when the secreted neuropeptide hormones galanin (GAL, PANTHER:PTHR16839:SF1; a 29- to 30-residue peptide sharing a strictly conserved N-terminal Trp2-Asn5-Tyr9 pharmacophore) and galanin-like peptide (GALP, PANTHER:PTHR20950:SF1; a 60-residue hypothalamic neuropeptide whose residues 9-21 are identical to galanin residues 1-13) bind and activate the seven-transmembrane G protein-coupled galanin receptors GALR1 (PANTHER:PTHR24230:SF31), GALR2 (PANTHER:PTHR24230:SF13), and GALR3 (PANTHER:PTHR24230:SF17) at the plasma membrane of central and peripheral neurons, pituitary cells, and pancreatic islet cells. Agonist-bound GALR1 and GALR3 couple primarily to pertussis-toxin-sensitive Gi/o heterotrimeric G proteins (exemplified by GNAI1, PANTHER:PTHR10218:SF359) to inhibit adenylate cyclase and open GIRK channels, whereas GALR2 couples primarily to Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to activate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), mobilize IP3-sensitive intracellular Ca2+ stores, and modulate nociception, feeding, neuroendocrine secretion, and neuronal excitability. status: DRAFT evidence: - source_id: GO:0090663 title: galanin-activated signaling pathway statement: >- The module is grounded in the GO biological process term for the galanin-activated signaling pathway (GO:0090663: the series of molecular signals generated as a consequence of a galanin receptor binding to its physiological ligand). - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Galanin is a 30-amino acid inhibitory neuropeptide encoded by the GAL gene (Schmidt WE et al, 1991; Bersani M et al, 1991). It is involved in a number of physiological processes such as regulation of food intake, metabolism and reproduction and regulation of neurotransmitter and hormone release. These actions are mediated via the galanin receptor which binds galanin. Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes that galanin binds and activates the three human galanin receptor subtypes GALR1, GALR2, and GALR3. - source_id: PMID:24602615 title: Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells. supporting_text: >- Moreover, the inositol-1,4,5-triphosphate receptor (IP3R) was identified as the mediator responsible for increased intracellular Ca(2+) activating BK channels. 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. statement: >- Demonstrates that galanin binding to GALR2 activates the Gq/11-PLC-IP3-Ca2+ signaling cascade. - source_id: PMID:25691535 title: Galanin pathogenic mutations in temporal lobe epilepsy. supporting_text: >- Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. 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. statement: >- Demonstrates that wild-type human GAL acts as a direct peptide agonist of both GALR1 and GALR2. - source_id: PMID:10601261 title: Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus. supporting_text: >- The amino acid sequence of GALP-(9-21) was completely identical to that of galanin-(1-13). statement: >- Establishes galanin-like peptide (GALP) as a 60-residue endogenous neuropeptide sharing a conserved 13-residue core with galanin (GAL residues 1-13 = GALP residues 9-21) that binds and activates galanin receptors (preferentially GALR2 over GALR1). - source_id: PANTHER:PTN008359337 title: PAINT node PTN008359337 for galanin peptides (PTHR16839) statement: >- Local PAINT IBD node in PTHR16839 with propagated terms C:GO:0005576, C:GO:0030141, C:GO:0043025, F:GO:0005184, P:GO:0007189, P:GO:0007218; PAINT date 20260529. notes: >- Curated signaling-pathway module for the galanin-activated signaling pathway (GO:0090663) built with PANTHER FAMILY/subfamily selectors across the two endogenous galanin-family neuropeptide ligands GAL (PANTHER:PTHR16839:SF1) and GALP (PANTHER:PTHR20950:SF1), their cognate GPCRs GALR1 (PANTHER:PTHR24230:SF31), GALR2 (PANTHER:PTHR24230:SF13), and GALR3 (PANTHER:PTHR24230:SF17), and downstream Gi/o alpha (GNAI1, PANTHER:PTHR10218:SF359), Gq/11 alpha (GNAQ, PANTHER:PTHR10218:SF329), and phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12) effectors. module: id: galanin_signaling label: Galanin-activated signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway description: >- The series of molecular signals generated as a consequence of a galanin receptor (GALR1, GALR2, or GALR3) binding to one of its physiological ligands (galanin GAL or galanin-like peptide GALP). context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: galanin and galanin-like peptide ligand-receptor engagement node: id: galanin_receptor_engagement label: GAL and GALP engagement of galanin receptors GALR1, GALR2, and GALR3 module_type: REGULATORY_STEP description: >- Secreted mature galanin (GAL) and galanin-like peptide (GALP) bind the orthosteric binding pockets of the seven-transmembrane galanin receptors GALR1, GALR2, and GALR3 at the plasma membrane via their shared N-terminal galanin(1-13) pharmacophore. annotons: - id: gal_galanin_ligand label: GAL galanin neuropeptide ligand participant: selector_type: FAMILY family: preferred_term: Galanin peptides subfamily term: id: PANTHER:PTHR16839:SF1 label: GALANIN PEPTIDES representative_members: - preferred_term: GAL term: id: UniProtKB:P22466 label: Galanin peptides ancestral_nodes: - preferred_term: PAINT node PTN008359337 for galanin peptides term: id: PANTHER:PTN008359337 label: PTN008359337 description: >- Local PAINT IBD node in PTHR16839 with propagated terms C:GO:0005576, C:GO:0030141, C:GO:0043025, F:GO:0005184, P:GO:0007189, P:GO:0007218; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008359337 in PTHR16839. evidence: - source_id: file:interpro/panther/PTHR16839/PTHR16839-review.yaml title: PTHR16839 PANTHER family review statement: >- PTHR16839 review confirms family-wide GO:0005184 (neuropeptide hormone activity) and GO:0090663 (galanin-activated signaling pathway) across PANTHER:PTHR16839:SF1 (GAL). function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Primary endogenous galanin neuropeptide hormone that binds and activates all three galanin receptors (GALR1, GALR2, and GALR3) with nanomolar affinity to initiate galanin-activated GPCR signaling. evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- These actions are mediated via the galanin receptor which binds galanin. Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GAL as the endogenous neuropeptide agonist of GALR1, GALR2, and GALR3. - source_id: PMID:25691535 title: Galanin pathogenic mutations in temporal lobe epilepsy. supporting_text: >- 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. statement: >- Demonstrates direct agonist activity of human GAL at GALR1 and GALR2. - id: galp_galanin_like_peptide_ligand label: GALP galanin-like peptide ligand participant: selector_type: FAMILY family: preferred_term: Galanin-like peptide subfamily term: id: PANTHER:PTHR20950:SF1 label: GALANIN-LIKE PEPTIDE representative_members: - preferred_term: GALP term: id: UniProtKB:Q9UBC7 label: Galanin-like peptide evidence: - source_id: file:interpro/panther/PTHR20950/PTHR20950-review.yaml title: PTHR20950 PANTHER family review statement: >- PTHR20950 review confirms family-wide GO:0005184 (neuropeptide hormone activity) and GO:0090663 (galanin-activated signaling pathway) across PANTHER:PTHR20950:SF1 (GALP). function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Hypothalamic 60-residue galanin-family neuropeptide hormone sharing the conserved 13-residue galanin pharmacophore (GALP residues 9-21 identical to GAL residues 1-13) that binds and activates galanin receptors (preferentially GALR2 and GALR3) to initiate galanin-activated GPCR signaling. evidence: - source_id: PMID:10601261 title: Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus. supporting_text: >- The amino acid sequence of GALP-(9-21) was completely identical to that of galanin-(1-13). statement: >- Demonstrates that mature GALP(1-60) shares residues 9-21 with galanin(1-13) and selectively binds and activates galanin receptors (GALR2 > GALR1). - id: galr1_receptor label: GALR1 galanin receptor type 1 participant: selector_type: FAMILY family: preferred_term: Galanin receptor type 1 subfamily term: id: PANTHER:PTHR24230:SF31 label: GALANIN RECEPTOR TYPE 1 representative_members: - preferred_term: GALR1 term: id: UniProtKB:P47211 label: Galanin receptor type 1 evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GALR1 as a human galanin GPCR subtype. function: preferred_term: galanin receptor activity term: id: GO:0004966 label: galanin receptor activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane G protein-coupled galanin receptor type 1 that binds GAL and GALP and signals through inhibitory Gi/o heterotrimeric G proteins. evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GALR1 as a principal human galanin receptor. - id: galr2_receptor label: GALR2 galanin receptor type 2 participant: selector_type: FAMILY family: preferred_term: Galanin receptor type 2 subfamily term: id: PANTHER:PTHR24230:SF13 label: GALANIN RECEPTOR TYPE 2 representative_members: - preferred_term: GALR2 term: id: UniProtKB:O43603 label: Galanin receptor type 2 evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GALR2 as a human galanin GPCR subtype. function: preferred_term: galanin receptor activity term: id: GO:0004966 label: galanin receptor activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane G protein-coupled galanin receptor type 2 that binds both GAL and GALP with high affinity and signals primarily through Gq/11 and phospholipase C-beta. evidence: - source_id: PMID:24602615 title: Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells. supporting_text: >- 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. statement: >- Demonstrates GALR2 coupling to the PLC/IP3/Ca2+ pathway upon galanin binding. - id: galr3_receptor label: GALR3 galanin receptor type 3 participant: selector_type: FAMILY family: preferred_term: Galanin receptor type 3 subfamily term: id: PANTHER:PTHR24230:SF17 label: GALANIN RECEPTOR TYPE 3 representative_members: - preferred_term: GALR3 term: id: UniProtKB:O60755 label: Galanin receptor type 3 evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GALR3 as a human galanin GPCR subtype. function: preferred_term: galanin receptor activity term: id: GO:0004966 label: galanin receptor activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane G protein-coupled galanin receptor type 3 that binds GAL and GALP and signals through inhibitory Gi/o heterotrimeric G proteins. evidence: - source_id: Reactome:R-HSA-389026 title: Galanin receptors can bind galanin supporting_text: >- Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). statement: >- Establishes GALR3 as a principal human galanin receptor. - order: 2 role: Gi/o and Gq/11-phospholipase C-beta effector coupling node: id: galanin_g_protein_effector_coupling label: Gi/o and Gq/11-PLC-beta effector coupling downstream of GALR1/GALR2/GALR3 module_type: REGULATORY_STEP description: >- Agonist-activated GALR1 and GALR3 catalyze GDP-to-GTP exchange on inhibitory Gi/o alpha subunits (exemplified by GNAI1) to inhibit adenylate cyclase, whereas agonist-activated GALR2 catalyzes GDP-to-GTP exchange on Gq/11 alpha subunits (exemplified by GNAQ) to activate phospholipase C-beta (PLCB1) and generate IP3 and DAG. annotons: - id: gnai1_gi_alpha label: GNAI1 Gi alpha-1 subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily term: id: PANTHER:PTHR10218:SF359 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-1 representative_members: - preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Activated Gi/o alpha subunits inhibit adenylate cyclase and cAMP-dependent signaling. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway - preferred_term: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway term: id: GO:0007193 label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inhibitory Gi alpha subunit activated by ligand-bound GALR1 and GALR3 to inhibit adenylate cyclase and modulate potassium/calcium channels. evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Establishes that activated Gi/o alpha subunits signal by inhibiting adenylate cyclase. - id: gnaq_gq_alpha label: GNAQ Gq alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(q) subunit alpha subfamily term: id: PANTHER:PTHR10218:SF329 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(Q) SUBUNIT ALPHA representative_members: - preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha evidence: - source_id: Reactome:R-HSA-416476 title: G alpha (q) signalling events supporting_text: >- The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. statement: >- Activated Gq/11 alpha subunits stimulate phospholipase C-beta to trigger phosphoinositide hydrolysis and calcium mobilization. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Heterotrimeric Gq alpha subunit activated by ligand-bound GALR2 to stimulate phospholipase C-beta. evidence: - source_id: Reactome:R-HSA-416476 title: G alpha (q) signalling events supporting_text: >- The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. statement: >- Establishes that activated Gq/11 alpha subunits signal by stimulating phospholipase C-beta. - id: plcb1_phospholipase_c_beta label: PLCB1 phospholipase C-beta-1 effector participant: selector_type: FAMILY family: preferred_term: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily term: id: PANTHER:PTHR10336:SF12 label: 1-PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE PHOSPHODIESTERASE BETA-1 representative_members: - preferred_term: PLCB1 term: id: UniProtKB:Q9NQ66 label: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 evidence: - source_id: PMID:24602615 title: Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells. supporting_text: >- Moreover, the inositol-1,4,5-triphosphate receptor (IP3R) was identified as the mediator responsible for increased intracellular Ca(2+) activating BK channels. statement: >- GALR2 activation stimulates phospholipase C-beta to generate IP3 and mobilize intracellular Ca2+. function: preferred_term: phosphatidylinositol phospholipase C activity term: id: GO:0004435 label: phosphatidylinositol phospholipase C activity processes: - preferred_term: galanin-activated signaling pathway term: id: GO:0090663 label: galanin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Phospholipase C-beta effector activated by GTP-bound GNAQ downstream of GALR2 to generate IP3 and DAG. evidence: - source_id: PMID:24602615 title: Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells. supporting_text: >- 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. statement: >- Demonstrates PLC activation downstream of GALR2 in galanin-activated signaling. connections: - source: galanin_receptor_engagement target: galanin_g_protein_effector_coupling connection_type: CAUSES description: >- Binding of mature GAL or GALP to GALR1, GALR2, or GALR3 stabilizes the active receptor conformation that catalyzes GDP-to-GTP exchange on Gi/o (GALR1, GALR3) or Gq/11 (GALR2) heterotrimeric G proteins and activates downstream second-messenger effectors.