{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Galanin receptor 2 (GALR2) is emerging as a versatile mediator of galanin‐dependent signaling in both the central nervous system and peripheral tissues. In one of the earliest studies, an endogenous peptide—galanin‐like peptide (GALP)—was shown to preferentially bind GALR2 with high affinity, suggesting that GALR2 plays a key role in the neuromodulatory actions of galanin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the brain, GALR2 activation promotes neuroprotective and anti‐apoptotic effects. For example, exogenous galanin normally stimulates Akt and ERK phosphorylation in hippocampal neurons; this protective signaling is strikingly attenuated in animals carrying a loss‐of‐function mutation in GALR2, and genetic deletion of GALR2 has been associated with depressive‐like behavior in paradigms of stress and learned helplessness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " In addition, GALR2 has been implicated in the modulation of pain; studies using selective agonists (e.g., Gal2‐11) demonstrate that high concentrations of galanin acting via GALR2 can markedly inhibit the mechanosensitivity of nociceptive C‐fiber afferents, thereby contributing to its antinociceptive effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the realm of cancer biology, GALR2 appears to have a context‐specific role. On one hand, in neuroblastoma cells, high GALR2 expression can inhibit cell proliferation and induce apoptosis, supporting a tumor‐suppressor role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " On the other hand, in head and neck cancers, GALR2 activation mediates nerve–tumor crosstalk and promotes tumor progression by triggering signaling cascades—such as p38‐MAPK and RAP1B—that enhance proliferation, survival, and angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, emerging evidence indicates that endogenous ligands like spexin—which shares sequence similarity with galanin—can activate GALR2 (along with GALR3) to regulate aspects of adipocyte metabolism, suggesting a broader role in energy balance (not shown in all studies but supported by related work). Collectively, these findings underscore that GALR2 signaling is highly context‐dependent, mediating neuroprotective and mood‐regulating effects in the brain while exerting both tumor‐suppressive and tumor‐promoting influences in peripheral tissues. Such diverse functions highlight GALR2 as an attractive therapeutic target for conditions ranging from neurodegenerative and mood disorders to pain management and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "T Ohtaki, S Kumano, Y Ishibashi, et al. 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