Associate editor: S.D. Brain The galanin peptide family: Receptor pharmacology, pleiotropic biological actions, and implications in health and disease Roland Lang a,b , Andrew L. Gundlach c,d , Barbara Kofler a, ⁎ a Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Muellner-Hauptstrasse 48, 5020 Salzburg, Austria b Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, Muellner-Hauptstrasse 48, 5020 Salzburg, Austria c Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia d Department of Anatomy and Cell Biology, The University of Melbourne, Victoria 3010, Australia Abstract The galanin peptide family consists of the “parental” galanin, galanin-message-associated peptide (GMAP) which derives from the same peptide precursor gene product as galanin, galanin-like peptide (GALP) encoded by a different gene, and the recently discovered peptide alarin which is encoded by a splice variant of the GALP gene. The galanin receptor family currently comprises 3 members, GalR1, GalR2, and GalR3, which are all G-protein-coupled receptors. This review will provide an overview of the comprehensive, pharmacological characterization of endogenous and synthetic galanin receptor ligands and their interactions with the galanin receptors, a summary of the various (pleiotropic) biological actions of galanin and GALP (and alarin), and briefly discuss the implications of pathological changes for health and disease and potential clinical therapeutics. Since its discovery more than 20 years ago, a large number of putative physiological functions have been ascribed to galanin, and active research still continues to validate these functions and determine their importance for physiology and pathology. Since the more recent identification of GALP, considerable research has identified functions for this peptide in the central nervous system (CNS), but the identity of its preferred, native receptor is still unknown. Little is known of the role of alarin apart from evidence of its expression and a vasoactive action in the skin. The wide range of functions of the galanin peptide family indicates an essential role for galanin signaling in “mind and body homeostasis” and a potential therapeutic efficacy in a variety of human diseases, particularly epilepsy, Alzheimer's disease, and diabetes. © 2007 Elsevier Inc. All rights reserved. Keywords: Galanin; Galanin-like peptide; Alarin; GalR1-3; G-protein coupled receptors Abbreviations: ACh, acetylcholine; ACTH, adrenocorticotrophic hormone; BNST, bed nucleus of the stria terminalis; cAMP, cyclic adenosine monophosphate; CHO, Chinese hamster ovary cells; CNS, central nervous system; D-β-H, dopamine-β-hydroxylase; DRG, dorsal root ganglia; EPM, elevated plus-maze; Galanin- KO, galanin knockout; Galanin-LI, galanin-like immunoreactivity; Galanin-OE, galanin overexpressing; GALP, galanin-like peptide; GalR1/2/3, galanin receptor 1/2/3; GalR1-KO, galanin receptor 1 knockout; GI, gastrointestinal; GIRK, G-protein-regulated inwardly rectifying K + channel; GMAP, galanin message- associated peptide; GnRH, gonadotropin-releasing hormone; GPCR, G-protein-coupled receptor; HEK, human embryonic kidney 293 cells; LH, luteinizing hormone; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; NPY, neuropeptide Y; pCREB, phosphorylated cAMP response element binding protein; PKC, protein kinase C; PLC, phospholipase C; POMC, pro-opiomelanocortin; PTX, pertussis toxin; PVN, paraventricular nucleus; SSSE, self-sustaining status epilepticus. Contents 1. Galanin family peptides ..................................... 178 2. Galanin receptors and their native and synthetic ligands .................... 179 2.1. Native galanin peptides .................................. 179 2.2. Galanin fragments .................................... 180 Pharmacology & Therapeutics 115 (2007) 177 – 207 www.elsevier.com/locate/pharmthera ⁎ Corresponding author. Tel.: +43 662 4482 4741; fax: +43 662 4482 4765. E-mail address: b.kofler@salk.at (B. Kofler). 0163-7258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2007.05.009