Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell

Danusa Menegaz, D. Walker Hagan, Joana Almaça, Chiara Cianciaruso, Rayner Rodriguez-Diaz, Judith Molina, Robert M. Dolan, Matthew W. Becker, Petra C. Schwalie, Rita Nano, Fanny Lebreton, Chen Kang, Rajan Sah, Herbert Y. Gaisano, Per Olof Berggren, Steinunn Baekkeskov, Alejandro Caicedo, Edward A. Phelps

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Pancreatic beta cells synthesize and secrete the neurotransmitter GABA (γ-aminobutyric acid) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory-vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here, we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel, functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from patients with type 1 and type 2 diabetes, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.

Original languageEnglish (US)
Pages (from-to)1110-1126
Number of pages17
JournalNature Metabolism
Volume1
Issue number11
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

Cite this

Menegaz, D., Hagan, D. W., Almaça, J., Cianciaruso, C., Rodriguez-Diaz, R., Molina, J., Dolan, R. M., Becker, M. W., Schwalie, P. C., Nano, R., Lebreton, F., Kang, C., Sah, R., Gaisano, H. Y., Berggren, P. O., Baekkeskov, S., Caicedo, A., & Phelps, E. A. (2019). Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell. Nature Metabolism, 1(11), 1110-1126. https://doi.org/10.1038/s42255-019-0135-7