Secreted neuroendocrine peptide precursor synthesized predominantly in hypothalamic arcuate nucleus neurons and posterior pituitary pituicytes. Proteolytically processed from a 116-amino-acid preproprotein into the 60-residue mature galanin-like peptide (GALP, residues 25-84), whose central segment (residues 9-21 of mature GALP) is 100% identical to the N-terminal 13-residue receptor-activating pharmacophore of galanin (Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro). Mature GALP acts as an endogenous neuropeptide hormone agonist that binds and activates the G protein-coupled galanin receptors — preferentially Gq/11-coupled GALR2 and Gi/o-coupled GALR3, with lower affinity for GALR1 — to initiate the galanin-activated signaling pathway and link metabolic state to feeding behavior and reproductive neuroendocrine secretion. Alternative splicing skipping exon 3 generates isoform 2, which is processed into alarin, a 25-residue vasoactive neuropeptide lacking the galanin-homologous domain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005179 hormone activity | IEA GO_REF:0000002 | MODIFY | Summary: Valid InterPro2GO mapping from the galanin conserved site (IPR008174), but too general: mature GALP is a hypothalamic neuropeptide hormone whose molecular function is more precisely captured by neuropeptide hormone activity (GO:0005184). Reason: GALP is synthesized and secreted by hypothalamic arcuate nucleus neurons and acts as a neuropeptide hormone agonist for galanin receptors (PMID:10601261). Replace parent GO:0005179 with the specific child term neuropeptide hormone activity (GO:0005184). Proposed replacements: neuropeptide hormone activity Supporting Evidence: PMID:10601261 We isolated a novel galanin-like peptide (GALP) from porcine hypothalamus by observing its activity for increasing [(35)S]GTPgammaS binding to a membrane preparation of GALR2-transfected cells. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative bare protein binding annotation from high-throughput yeast two-hybrid screening (SGTA, O43765). Reason: Per the protein-binding policy, bare GO:0005515 rows from high-throughput yeast two-hybrid screens (PMID:32296183, HuRI) are uninformative for a secreted neuropeptide precursor and are removed in favor of specific ligand activity (GO:0005184). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative bare protein binding annotation from high-throughput yeast two-hybrid screening (UBQLN2, Q9UHD9). Reason: Per the protein-binding policy, bare GO:0005515 rows from high-throughput yeast two-hybrid screens (PMID:32296183, HuRI) are uninformative for a secreted neuropeptide precursor and are removed in favor of specific ligand activity (GO:0005184). |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Core localization of secreted mature GALP in the extracellular space where it binds cell-surface galanin receptors. Reason: GALP carries a cleavable N-terminal signal peptide (residues 1-24) and is secreted into the extracellular space as a 60-residue mature neuropeptide hormone (PMID:10601261). Supporting Evidence: PMID:10601261 A cloned porcine GALP cDNA indicated that GALP was processed from a 120-amino acid GALP precursor protein. The structures of rat and human GALP-(1-60) were deduced from cloned cDNA, which indicated that the amino acid sequences 1-24 and 41-53 were highly conserved between humans, rats, and pigs. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | MODIFY | Summary: Logical inference from hormone activity (GO:0005179), but too general: GALP specifically initiates the galanin-activated signaling pathway (GO:0090663). Reason: Mature GALP shares the conserved 13-residue pharmacophore of galanin (GALP residues 9-21 = galanin residues 1-13) and binds and activates GALR2, GALR1, and GALR3 to initiate the galanin-activated signaling pathway (GO:0090663; PMID:10601261). Replace generic signal transduction (GO:0007165) with GO:0090663 (proposed as a NEW annotation below). Proposed replacements: galanin-activated signaling pathway Supporting Evidence: PMID:10601261 Receptor binding studies revealed that porcine GALP-(1-60) had a high affinity for the GALR2 receptor (IC(50) = 0.24 nM) and a lower affinity for the GALR1 receptor (IC(50) = 4.3 nM). In contrast, galanin showed high affinity for the GALR1 (IC(50) = 0.097 nM) and GALR2 receptors (IC(50) = 0.48 nM). GALP is therefore an endogenous ligand that preferentially binds the GALR2 receptor, whereas galanin is relatively non-selective. |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Valid Ensembl Compara transfer from rat Galp reflecting hormonal regulation of hypothalamic GALP expression; non-core upstream regulatory context. Reason: Hypothalamic Galp expression is regulated by metabolic hormones (leptin, insulin, thyroid hormone) in rodents, which represents upstream transcriptional regulation of the precursor rather than the core receptor-signaling function of the mature peptide. |
| GO:0032868 response to insulin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Valid Ensembl Compara transfer from rat Galp reflecting insulin-mediated regulation of arcuate nucleus Galp mRNA; non-core upstream regulatory context. Reason: Reflects upstream hormonal regulation of hypothalamic Galp expression in response to circulating insulin rather than a direct biochemical activity of the GALP peptide. |
| GO:0042595 behavioral response to starvation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Valid phylogenetic transfer seeded from mouse Galp, reflecting physiological regulation of feeding and energy balance during fasting. Reason: Arcuate nucleus GALP neurons are suppressed by fasting and link energy stores to feeding behavior downstream of galanin receptor signaling; retained as a valid organismal phenotype downstream of the core signaling pathway. |
| GO:0005184 neuropeptide hormone activity | ISS PMID:10601261 Isolation and cDNA cloning of a novel galanin-like peptide (... | NEW | Summary: Mature GALP-(1-60) is a secreted hypothalamic neuropeptide hormone carrying the conserved 13-residue galanin pharmacophore (GALP residues 9-21) that activates G protein-coupled galanin receptors. Reason: Human GALP-(1-60) shares the conserved receptor-binding pharmacophore (residues 1-24 highly conserved across human, rat, and pig; residues 9-21 identical to galanin 1-13) that stimulates [35S]GTPgammaS binding at GALR2 (IC50 = 0.24 nM) and GALR1 (IC50 = 4.3 nM; PMID:10601261). Human GALP currently carries only generic IEA hormone activity (GO:0005179); adding GO:0005184 (neuropeptide hormone activity) captures its specific molecular function. Supporting Evidence: PMID:10601261 We isolated a novel galanin-like peptide (GALP) from porcine hypothalamus by observing its activity for increasing [(35)S]GTPgammaS binding to a membrane preparation of GALR2-transfected cells. The peptide had 60 amino acid residues and a non-amidated C terminus. The amino acid sequence of GALP-(9-21) was completely identical to that of galanin-(1-13). |
| GO:0090663 galanin-activated signaling pathway | ISS PMID:10601261 Isolation and cDNA cloning of a novel galanin-like peptide (... | NEW | Summary: Mature GALP-(1-60) binds and activates the G protein-coupled galanin receptors (preferentially GALR2, and also GALR1 and GALR3) via its conserved galanin-(1-13) core motif to initiate the galanin-activated signaling pathway. Reason: Human GALP currently carries only generic IEA signal transduction (GO:0007165). Ohtaki et al. (PMID:10601261) cloned human, rat, and porcine GALP cDNAs and demonstrated that GALP-(1-60), whose residues 9-21 are 100% identical to galanin-(1-13), acts as a high-affinity endogenous agonist for GALR2 (IC50 = 0.24 nM) and GALR1 (IC50 = 4.3 nM), stimulating [35S]GTPgammaS binding. Supporting Evidence: PMID:10601261 Receptor binding studies revealed that porcine GALP-(1-60) had a high affinity for the GALR2 receptor (IC(50) = 0.24 nM) and a lower affinity for the GALR1 receptor (IC(50) = 4.3 nM). In contrast, galanin showed high affinity for the GALR1 (IC(50) = 0.097 nM) and GALR2 receptors (IC(50) = 0.48 nM). GALP is therefore an endogenous ligand that preferentially binds the GALR2 receptor, whereas galanin is relatively non-selective. |
Loading supporting content…
Download this section (compressed HTML)Q: What is the cognate cell-surface receptor for the alternatively spliced GALP isoform 2 peptide alarin (which lacks the exon 3-encoded galanin-(1-13) pharmacophore and does not bind GALR1-3)?
Q: How do the conserved C-terminal residues 41-53 of mature GALP-(1-60) interact with the extracellular loops of GALR2 and GALR3 to confer receptor subtype selectivity over GALR1?
Experiment: Determine cryo-EM structures of human GALP-(1-60) bound to GALR2-Gq and GALR1-Gi1 complexes to define how the C-terminal tail of GALP (residues 22-60) confers ~18-fold selectivity for GALR2 over GALR1 despite sharing an identical 13-residue N-terminal pharmacophore with galanin.
Hypothesis: Extracellular loop 2/3 contacts with the conserved C-terminal segment of GALP (residues 41-53) selectively stabilize the active conformation of GALR2 relative to GALR1.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)