{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n GPR26 is a brain‐specific orphan G protein–coupled receptor that exhibits constitutive activity by elevating intracellular cAMP and is predominantly expressed in regions such as the striatum, pons, cerebellum, and cortex."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Functional studies in mice have revealed that loss of GPR26 leads to significant behavioral alterations; for example, Gpr26 knockout animals display increased anxiety‐ and depression‐like behaviors that are associated with reduced CREB phosphorylation in the central amygdala."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, GPR26 plays a critical role in maintaining energy homeostasis, as its deficiency causes hyperphagia, hypometabolism, and early onset obesity with accompanying metabolic disturbances—findings that correlate with increased hypothalamic AMPK activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In the oncological arena, epigenetic silencing of GPR26 has been observed in gliomas and glioblastomas, suggesting that it may function as a tumor suppressor by promoting differentiation (via cAMP‐mediated signaling), with lower expression levels linked to more aggressive disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Consistent with these findings, elevated GPR26 expression has been associated with antitumor activity in liver cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Beyond these roles, molecular analyses have implicated GPR26 in the formation or degradation of intranuclear inclusions in neurodegenerative conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and its deletion has been linked to inner ear defects in animal models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Together, these studies indicate that GPR26 is a multifunctional receptor involved in the regulation of emotional behavior, energy balance, and cell differentiation, positioning it as a promising target for therapeutic interventions in neuropsychiatric, metabolic, and oncological disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "D K Lee, T Nguyen, K R Lynch, et al. 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