Galanin Receptors in the Central Nervous System: Exploring Ligand Interactions, Signal Transduction, and Potential Clinical Implications

Galanin is a highly conserved neuropeptide widely expressed in the central nervous system (CNS), where it regulates neurotransmission, neuroplasticity, and neuroendocrine functions. Its effects are mediated through three G protein-coupled galanin receptor subtypes, GalR1, GalR2, and GalR3, each exhibiting distinct tissue distributions, ligand affinities, and intracellular signaling mechanisms. Endogenous ligands, including galanin, galanin-like peptide (GALP), and spexin, interact with these receptors to trigger receptor-specific pathways, such as adenylyl cyclase (AC) inhibition (GalR1/GalR3) and phospholipase C-mediated calcium signaling (GalR2), enabling modulation of neuronal excitability, neurotransmitter release, and cell survival. Exogenous ligands, including peptide analogs and non-peptide agonists, have further elucidated receptor function and highlighted opportunities for pharmacological intervention. Preclinical evidence demonstrates that targeting galanin receptors (GalRs) can influence mood, cognition, pain perception, epilepsy, metabolic regulation, and neuroprotection, suggesting therapeutic potential across diverse CNS disorders. By integrating knowledge of ligand-receptor interactions and downstream signaling, this review highlights the central role of GalRs in CNS physiology and their emerging relevance as targets for clinical applications.