Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila

• Published in: PloS one 2010-12, Vol.5 (12), p.e15780-e15780
• Main Authors: Enell, Lina E, Kapan, Neval, Söderberg, Jeannette A E, Kahsai, Lily, Nässel, Dick R
• Format: Article
• Language: English
• Subjects: Animals; Behavior; Biology; Biosynthesis; Brain; Brain - metabolism; Carbohydrate metabolism; Carbohydrates; Coronary vessels; Drosophila; Drosophila melanogaster; Functional Zoomorphology; funktionell zoomorfologi; G proteins; GABA; Gene expression; Genomes; Homeostasis; Humans; Immunofluorescence; Immunohistochemistry - methods; Insects; Insulin; Insulin - metabolism; Interneurons; Life span; Lipid Metabolism; Male; Mediation; Medicine; Metabolism; Metabotropic receptors; Microscopy, Fluorescence - methods; Neurons; Neuropeptides; Peptides; Physiological aspects; Potassium channels; Potassium Channels - chemistry; Receptors; Receptors, GABA - metabolism; Receptors, GABA-A - metabolism; Receptors, GABA-B - metabolism; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Rodents; Signal Transduction; Signaling; Stress; Stress (Physiology); Stress (Psychology); Stresses; Zoology; γ-Aminobutyric acid A receptors; γ-Aminobutyric acid B receptors; γ-Aminobutyric acid receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015780

Insulin-like peptides (ILPs) regulate growth, reproduction, metabolic homeostasis, life span and stress resistance in worms, flies and mammals. A set of insulin producing cells (IPCs) in the Drosophila brain that express three ILPs (DILP2, 3 and 5) have been the main focus of interest in hormonal DILP signaling. Little is, however, known about factors that regulate DILP production and release by these IPCs. Here we show that the IPCs express the metabotropic GABA(B) receptor (GBR), but not the ionotropic GABA(A) receptor subunit RDL. Diminishing the GBR expression on these cells by targeted RNA interference abbreviates life span, decreases metabolic stress resistance and alters carbohydrate and lipid metabolism at stress, but not growth in Drosophila. A direct effect of diminishing GBR on IPCs is an increase in DILP immunofluorescence in these cells, an effect that is accentuated at starvation. Knockdown of irk3, possibly part of a G protein-activated inwardly rectifying K(+) channel that may link to GBRs, phenocopies GBR knockdown in starvation experiments. Our experiments suggest that the GBR is involved in inhibitory control of DILP production and release in adult flies at metabolic stress and that this receptor mediates a GABA signal from brain interneurons that may convey nutritional signals. This is the first demonstration of a neurotransmitter that inhibits insulin signaling in its regulation of metabolism, stress and life span in an invertebrate brain.