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1 Cambridge Institute for Medical Research, University of Cambridge, Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK
The incretin hormone, glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells following food ingestion. Its secretion is triggered by a range of nutrients, including fats, carbohydrates and proteins. We reported previously that Na+-dependent glutamine uptake triggered electrical activity and GLP-1 release from the L-cell model line GLUTag. However, whereas alanine also triggered membrane depolarization and GLP-1 secretion, the response was Na+ independent. A range of alanine analogues, including D-alanine, ß-alanine, glycine and L-serine, but not D-serine, triggered similar depolarizing currents and elevation of intracellular [Ca2+], a sensitivity profile suggesting the involvement of glycine receptors. In support of this idea, glycine-induced currents and GLP-1 release were blocked by strychnine, and currents showed a 58.5 mV shift in reversal potential per 10-fold change in [Cl–], consistent with the activation of a Cl–-selective current. GABA, an agonist of related Cl– channels, also triggered Cl– currents and secretion, which were sensitive to picrotoxin. GABA-triggered [Ca2+]i increments were abolished by bicuculline and partially impaired by (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), suggesting the involvement of both GABAA and GABAC receptors. Expression of GABAA, GABAC and glycine receptor subunits was confirmed by RT-PCR. Glycine-triggered GLP-1 secretion was impaired by bumetanide but not bendrofluazide, suggesting that a high intracellular [Cl–] maintained by Na+–K+–2Cl– cotransporters is necessary for the depolarizing response to glycine receptor ligands. Our results suggest that GABA and glycine stimulate electrical activity and GLP-1 release from GLUTag cells by ligand-gated ion channel activation, a mechanism that might be important in responses to endogenous ligands from the enteric nervous system or dietary sources.
(Received 19 September 2005;
accepted after revision 12 October 2005;
first published online 13 October 2005)
Corresponding author F. M. Gribble: Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. Email: fmg23{at}cam.ac.uk
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