GAL Curation Notes (Human Galanin Peptides, UniProtKB:P22466)

Summary of Gene Function

• Gene symbol / ID: GAL (UniProtKB:P22466, HGNC:4114)
• PANTHER family: PANTHER:PTHR16839:SF1 (GALANIN PEPTIDES, within PANTHER:PTHR16839 GALANIN; root PAINT node PANTHER:PTN008359337).
• Preprohormone processing: Synthesized as a 123-amino-acid preprogalanin precursor (signal peptide residues 1-19; propeptide residues 20-32) that is cleaved at dibasic sites by prohormone convertases within neuronal and neuroendocrine secretory granules (GO:0030141) to yield two mature secreted peptides:
• Galanin (residues 33-62; 30 amino acids in human, uniquely carrying a C-terminal non-amidated Ser30 compared with 29-residue amidated galanin in other vertebrates) PMID:1722333.
• Galanin message-associated peptide (GMAP) (residues 65-123; 59 amino acids).
• Signaling mechanism: Mature galanin acts as a secreted neuropeptide hormone (GO:0005184 neuropeptide hormone activity, child of GO:0005179 hormone activity and GO:0048018 receptor ligand activity) whose strictly conserved N-terminal 1-13 pharmacophore (GWTLNSAGYLLGP) binds and activates all three seven-transmembrane G protein-coupled galanin receptors: GALR1, GALR2, and GALR3 (GO:0090663 galanin-activated signaling pathway) [PMID:1370155, PMID:24602615, PMID:25691535, Reactome:R-HSA-389026].
• GALR1 and GALR3 couple to pertussis-toxin-sensitive inhibitory Gi/o heterotrimeric G proteins (GNAI1/GNAI2/GNAI3) to inhibit adenylate cyclase and open GIRK potassium channels (GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway).
• GALR2 couples primarily to Gq/11 heterotrimeric G proteins (GNAQ) to activate phospholipase C-beta, generate IP3, and release Ca2+ from ER stores through IP3 receptors, facilitating BK channels and modulating neuronal excitability (GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway) [PMID:24602615, Reactome:R-HSA-389026].
• Physiological roles: Inhibits glucose-stimulated insulin secretion from pancreatic beta cells (GO:0032024 / GO:0046676) with subnanomolar potency (ED50 < 1 nM) PMID:1370155, modulates nociception and inflammatory pain (GO:0019233), regulates feeding behavior, smooth muscle contraction, and hippocampal/cortical seizure susceptibility (de novo p.Ala39Glu mutation in mature galanin causes temporal lobe epilepsy by converting galanin into a GALR1 antagonist and weakening GALR2 agonism) PMID:25691535.

Key Curation Corrections & Ligands in Signaling Pathways Assessment (Tranche 4C)

1. Ligand-vs-receptor MF mis-annotation (GO:0004966 galanin receptor activity): Human GAL is annotated with GO:0004966 (galanin receptor activity, IMP from PMID:25691535). In PMID:25691535, the authors assayed wild-type and p.Ala39Glu mutant galanin peptide on cells expressing GALR1 and GALR2; GAL is the secreted neuropeptide hormone ligand, not the transmembrane receptor! We MODIFY GO:0004966 to {GO:0005184, GO:0031764, GO:0031765} (and MODIFY GO:0005179 hormone activity, IEA GO_REF:0000002, to GO:0005184 neuropeptide hormone activity).
2. Tissue-restricted adrenocortical cAMP signaling (GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway): Human GAL carries an IDA annotation (PMID:17982695) and an IBA annotation (GO_REF:0000033, seeded from UniProtKB:P22466 at PANTHER:PTN008359337) for GO:0007189. While GALR1 and GALR3 canonically couple to inhibitory Gi/o proteins to inhibit adenylate cyclase (GO:0007193) and GALR2 couples to Gq/11 to activate phospholipase C (GO:0007200) [Reactome:R-HSA-389026, PMID:24602615], PMID:17982695 directly demonstrated in dispersed human adrenocortical cells expressing GALR1 (where GALR2 and GALR3 were undetectable) that 10 nM galanin enhanced cyclic-AMP production and cortisol secretion in a manner abolished by the adenylate cyclase inhibitor SQ-22536 ("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)."). We therefore retain both GO:0007189 rows as KEEP_AS_NON_CORE representing this tissue-restricted adrenocortical signaling branch.
3. Category B pathway gap (GO:0090663 galanin-activated signaling pathway): GO:0090663 currently has only the receptors GALR2 and GALR3 annotated in human/mouse/rat and zero ligand annotations across all species. We ACCEPT GO:0007218 (neuropeptide signaling pathway, IBA GO_REF:0000033) and GO:0031764/GO:0031765/GO:0031766 (type 1/2/3 galanin receptor binding, IDA PMID:24517231), MODIFY GO:0007165 (signal transduction, IDA PMID:24602615) and GO:0045944 (positive regulation of transcription by RNA polymerase II, IDA PMID:24517231) to GO:0090663 (galanin-activated signaling pathway), and add a NEW (IC) annotation for GO:0090663 supported by PMID:25691535, PMID:24602615, and PMID:24517231 (inferred from GO:0031764, GO:0031765, and GO:0031766), linking GAL to MODULE:galanin_signaling.