Galanin-activated signaling pathway module

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.

MODULE:galanin_signalingDRAFTSignaling Pathwaymodules/galanin_signaling.yaml
galanin-activated signaling pathwayGO:0090663
GO:0090663
galanin-activated signaling pathway
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).
Reactome:R-HSA-389026
Galanin receptors can bind galanin
Establishes that galanin binds and activates the three human galanin receptor subtypes GALR1, GALR2, and GALR3.
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).
PMID:24602615
Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells.
Demonstrates that galanin binding to GALR2 activates the Gq/11-PLC-IP3-Ca2+ signaling cascade.
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.
PMID:25691535
Galanin pathogenic mutations in temporal lobe epilepsy.
Demonstrates that wild-type human GAL acts as a direct peptide agonist of both GALR1 and GALR2.
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.
PMID:10601261
Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus.
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).
The amino acid sequence of GALP-(9-21) was completely identical to that of galanin-(1-13).
PANTHER:PTN008359337
PAINT node PTN008359337 for galanin peptides (PTHR16839)
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.

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.

3Nodes
2Parts
0Variant Sets
0Variants
8Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:galanin_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 9 evidence or coverage gap(s) (16 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
gal_galanin_ligand GAL
UniProtKB:P22466
Family Representative 		neuropeptide hormone activity
GO:0005184 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
galp_galanin_like_peptide_ligand GALP
UniProtKB:Q9UBC7
Family Representative 		neuropeptide hormone activity
GO:0005184 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
galr1_receptor GALR1
UniProtKB:P47211
Family Representative 		galanin receptor activity
GO:0004966 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
galr2_receptor GALR2
UniProtKB:O43603
Family Representative 		galanin receptor activity
GO:0004966 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
galr3_receptor GALR3
UniProtKB:O60755
Family Representative 		galanin receptor activity
GO:0004966 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gnai1_gi_alpha GNAI1
UniProtKB:P63096
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gnaq_gq_alpha GNAQ
UniProtKB:P50148
Family Representative 		G protein activity
GO:0003925 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plcb1_phospholipase_c_beta PLCB1
UniProtKB:Q9NQ66
Family Representative 		phosphatidylinositol phospholipase C activity
GO:0004435 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gal_galanin_ligand Galanin peptides subfamily
PANTHER:PTHR16839:SF1
Family 		neuropeptide hormone activity
GO:0005184 		Family Supported
Family review supports GO:0005184 FAMILY_WIDE. All members of PANTHER:PTHR16839 (SF1 GAL) are secreted neuropeptide hormones enabling GO:0005184.
galp_galanin_like_peptide_ligand Galanin-like peptide subfamily
PANTHER:PTHR20950:SF1
Family 		neuropeptide hormone activity
GO:0005184 		Family Supported
Family review supports GO:0005184 FAMILY_WIDE. All members of PANTHER:PTHR20950 (SF1 GALP) are secreted hypothalamic/pituitary neuropeptide hormones enabling GO:0005184.
galr1_receptor Galanin receptor type 1 subfamily
PANTHER:PTHR24230:SF31
Family 		galanin receptor activity
GO:0004966 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24230:SF31.
galr2_receptor Galanin receptor type 2 subfamily
PANTHER:PTHR24230:SF13
Family 		galanin receptor activity
GO:0004966 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24230:SF13.
galr3_receptor Galanin receptor type 3 subfamily
PANTHER:PTHR24230:SF17
Family 		galanin receptor activity
GO:0004966 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24230:SF17.
gnai1_gi_alpha Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily
PANTHER:PTHR10218:SF359
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF359.
gnaq_gq_alpha Guanine nucleotide-binding protein G(q) subunit alpha subfamily
PANTHER:PTHR10218:SF329
Family 		G protein activity
GO:0003925 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10218:SF329.
plcb1_phospholipase_c_beta 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily
PANTHER:PTHR10336:SF12
Family 		phosphatidylinositol phospholipase C activity
GO:0004435 		Family Supported
Family review supports GO:0004435 FAMILY_WIDE. Every reviewed member (fungal PLC1/plc1, PLCG1, PLCG2) accepts it. fgfr_signaling selects SF173 (PLCG1) and myo_inositol_and_inositol_phosphate_biosynthesis selects SF36 (fungal PLC).

Gene-review completeness (4/8 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 4 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
GAL P22466 ✓ ✓ ✗
GALP Q9UBC7 ✓ ✓ ✗
GNAI1 P63096 ✓ 140/146 ✗
GNAQ P50148 ✓ 111/121 ✗
GALR2 O43603 ✗ — —
GALR3 O60755 ✗ — —
GALR1 P47211 ✗ — —
PLCB1 Q9NQ66 ✗ — —

Details

Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829
Galanin-activated signaling pathwaySignaling Pathwaygalanin_signaling
galanin-activated signaling pathwayGO:0090663
Context
EuteleostomiNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829

Connections

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.
Part 1: galanin and galanin-like peptide ligand-receptor engagement
GAL and GALP engagement of galanin receptors GALR1, GALR2, and GALR3Regulatory Stepgalanin_receptor_engagement

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

GAL galanin neuropeptide ligand
gal_galanin_ligand
Participant: Family: Galanin peptides subfamily
Family:
Galanin peptides subfamilyPANTHER:PTHR16839:SF1
Representative Members: GALUniProtKB:P22466

Function

neuropeptide hormone activityGO:0005184

Processes

galanin-activated signaling pathwayGO:0090663

Locations

extracellular regionGO:0005576

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.

Reactome:R-HSA-389026
Galanin receptors can bind galanin
Establishes GAL as the endogenous neuropeptide agonist of GALR1, GALR2, and GALR3.
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).
PMID:25691535
Galanin pathogenic mutations in temporal lobe epilepsy.
Demonstrates direct agonist activity of human GAL at GALR1 and GALR2.
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.
GALP galanin-like peptide ligand
galp_galanin_like_peptide_ligand
Participant: Family: Galanin-like peptide subfamily
Family:
Galanin-like peptide subfamilyPANTHER:PTHR20950:SF1
Representative Members: GALPUniProtKB:Q9UBC7

Function

neuropeptide hormone activityGO:0005184

Processes

galanin-activated signaling pathwayGO:0090663

Locations

extracellular regionGO:0005576

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.

PMID:10601261
Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus.
Demonstrates that mature GALP(1-60) shares residues 9-21 with galanin(1-13) and selectively binds and activates galanin receptors (GALR2 > GALR1).
The amino acid sequence of GALP-(9-21) was completely identical to that of galanin-(1-13).
GALR1 galanin receptor type 1
galr1_receptor
Participant: Family: Galanin receptor type 1 subfamily
Family:
Galanin receptor type 1 subfamilyPANTHER:PTHR24230:SF31
Representative Members: GALR1UniProtKB:P47211

Function

galanin receptor activityGO:0004966

Processes

galanin-activated signaling pathwayGO:0090663

Locations

plasma membraneGO:0005886

Seven-transmembrane G protein-coupled galanin receptor type 1 that binds GAL and GALP and signals through inhibitory Gi/o heterotrimeric G proteins.

Reactome:R-HSA-389026
Galanin receptors can bind galanin
Establishes GALR1 as a principal human galanin receptor.
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).
GALR2 galanin receptor type 2
galr2_receptor
Participant: Family: Galanin receptor type 2 subfamily
Family:
Galanin receptor type 2 subfamilyPANTHER:PTHR24230:SF13
Representative Members: GALR2UniProtKB:O43603

Function

galanin receptor activityGO:0004966

Processes

galanin-activated signaling pathwayGO:0090663

Locations

plasma membraneGO:0005886

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.

PMID:24602615
Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells.
Demonstrates GALR2 coupling to the PLC/IP3/Ca2+ pathway upon galanin binding.
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.
GALR3 galanin receptor type 3
galr3_receptor
Participant: Family: Galanin receptor type 3 subfamily
Family:
Galanin receptor type 3 subfamilyPANTHER:PTHR24230:SF17
Representative Members: GALR3UniProtKB:O60755

Function

galanin receptor activityGO:0004966

Processes

galanin-activated signaling pathwayGO:0090663

Locations

plasma membraneGO:0005886

Seven-transmembrane G protein-coupled galanin receptor type 3 that binds GAL and GALP and signals through inhibitory Gi/o heterotrimeric G proteins.

Reactome:R-HSA-389026
Galanin receptors can bind galanin
Establishes GALR3 as a principal human galanin receptor.
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).
Part 2: Gi/o and Gq/11-phospholipase C-beta effector coupling
Gi/o and Gq/11-PLC-beta effector coupling downstream of GALR1/GALR2/GALR3Regulatory Stepgalanin_g_protein_effector_coupling

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

GNAI1 Gi alpha-1 subunit
gnai1_gi_alpha
Participant: Family: Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily
Family:
Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamilyPANTHER:PTHR10218:SF359
Representative Members: GNAI1UniProtKB:P63096

Function

G protein activityGO:0003925

Processes

galanin-activated signaling pathwayGO:0090663 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathwayGO:0007193

Locations

plasma membraneGO:0005886

Inhibitory Gi alpha subunit activated by ligand-bound GALR1 and GALR3 to inhibit adenylate cyclase and modulate potassium/calcium channels.

Reactome:R-HSA-418594
G alpha (i) signalling events
Establishes that activated Gi/o alpha subunits signal by inhibiting adenylate cyclase.
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).
GNAQ Gq alpha subunit
gnaq_gq_alpha
Participant: Family: Guanine nucleotide-binding protein G(q) subunit alpha subfamily
Family:
Guanine nucleotide-binding protein G(q) subunit alpha subfamilyPANTHER:PTHR10218:SF329
Representative Members: GNAQUniProtKB:P50148

Function

G protein activityGO:0003925

Processes

galanin-activated signaling pathwayGO:0090663 phospholipase C-activating G protein-coupled receptor signaling pathwayGO:0007200

Locations

plasma membraneGO:0005886

Heterotrimeric Gq alpha subunit activated by ligand-bound GALR2 to stimulate phospholipase C-beta.

Reactome:R-HSA-416476
G alpha (q) signalling events
Establishes that activated Gq/11 alpha subunits signal by stimulating phospholipase C-beta.
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.
PLCB1 phospholipase C-beta-1 effector
plcb1_phospholipase_c_beta
Participant: Family: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamily
Family:
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 subfamilyPANTHER:PTHR10336:SF12
Representative Members: PLCB1UniProtKB:Q9NQ66

Function

phosphatidylinositol phospholipase C activityGO:0004435

Processes

galanin-activated signaling pathwayGO:0090663

Locations

plasma membraneGO:0005886

Phospholipase C-beta effector activated by GTP-bound GNAQ downstream of GALR2 to generate IP3 and DAG.

PMID:24602615
Activation of galanin receptor 2 stimulates large conductance Ca(2+)-dependent K(+) (BK) channels through the IP3 pathway in human embryonic kidney (HEK293) cells.
Demonstrates PLC activation downstream of GALR2 in galanin-activated signaling.
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.