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

doi:10.1038/s42255-019-0135-7

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

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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 language	English
Pages (from-to)	1110-1126
Number of pages	17
Journal	Nature Metabolism
Volume	1
Issue number	11
DOIs	https://doi.org/10.1038/s42255-019-0135-7
State	Published - Nov 1 2019

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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

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title = "Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

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Menegaz, D, Hagan, DW, Almaça, J, Cianciaruso, C, Rodriguez-Diaz, R, Molina, J, Dolan, RM, Becker, MW, Schwalie, PC, Nano, R, Lebreton, F, Kang, C, Sah, R, Gaisano, HY, Berggren, PO, Baekkeskov, S, Caicedo, A & Phelps, EA 2019, 'Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell', Nature Metabolism, vol. 1, no. 11, pp. 1110-1126. https://doi.org/10.1038/s42255-019-0135-7

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T1 - Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell

AU - Menegaz, Danusa

AU - Hagan, D. Walker

AU - Almaça, Joana

AU - Cianciaruso, Chiara

AU - Rodriguez-Diaz, Rayner

AU - Molina, Judith

AU - Dolan, Robert M.

AU - Becker, Matthew W.

AU - Schwalie, Petra C.

AU - Nano, Rita

AU - Lebreton, Fanny

AU - Kang, Chen

AU - Sah, Rajan

AU - Gaisano, Herbert Y.

AU - Berggren, Per Olof

AU - Baekkeskov, Steinunn

AU - Caicedo, Alejandro

AU - Phelps, Edward A.

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AB - 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.

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

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