title: Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells.
abstract: OBJECTIVE
  Galanin is a widely expressed neuropeptide, which in the gut is thought to modulate gastrointestinal motility and secretion. We aimed to elucidate the poorly characterised mechanisms underlying the inhibitory effect of galanin and the potential involvement of G-protein coupled inwardly rectifying potassium, Kir 3, (GIRK) channels in glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) secretion.
  
  
  METHODS
  Purified murine L and K cells were analysed for expression of galanin receptors and GIRK subunits. Hormone secretion was measured from primary murine intestinal cultures. Intracellular cAMP was monitored in primary L cells derived from mice expressing the Epac2camps sensor under the control of the proglucagon promoter.
  
  
  RESULTS
  Galanin receptor 1 (GAL1, Galr1) and GIRK channel 1 (Kir 3.1, Kcnj3) and 4 (Kir 3.4, Kcnj5) mRNA expression was highly enriched in K and L cells. Galanin and a selective GAL1 receptor agonist (M617) potently inhibited GLP-1 and GIP secretion from primary small intestinal cultures. In L cells, galanin significantly inhibited the forskolin-induced cAMP response. The GIRK1/4 activator ML297 significantly reduced glucose-stimulated and IBMX-stimulated GLP-1 secretion but had no effect on GIP. The GIRK blocker tertiapin-Q did not impair galanin-mediated GLP-1 inhibition.
  
  
  CONCLUSIONS
  Galanin, acting via the GAL1 receptor and Gi -coupled signalling in L and K cells, is a potent inhibitor of GLP-1 and GIP secretion. Although GIRK1/4 channels are expressed in these cells, their activation does not appear to play a major role in galanin-mediated inhibition of incretin secretion.
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Arianna
authors.initials: A
authors.lastname: Psichas
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Glass
authors.affiliation: MRC Epidemiology Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019004:Galanin / Q000494:pharmacology*; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D044091:Receptor, Galanin, Type 1 / Q000235:genetics*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; C486707:Rapgef4 protein, mouse; D044091:Receptor, Galanin, Type 1; D005749:Gastric Inhibitory Polypeptide; D019004:Galanin; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP