Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters

Eskandari, Sepehr; Willford, Samantha L.; Anderson, Cynthia M.

doi:10.1007/978-3-319-55769-4_5

Cited by 16 publications

(18 citation statements)

References 176 publications

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“…These include proteins encoded for by Slc6A12 (betaine GABA transporter 1 [BGT1]), Slc6A13 (GABA transporter 2 [GAT2]), Slc6A6 (taurine transporter [TauT]), and Slc6A8 (creatine transporter [CRT]). BGT1 and GAT2 both co-transport 3 Na + , 1 Cl − , and GABA, moving 2 positive charges in the direction of GABA transport ( Eskandari et al, 2017 ). TauT co-transports 2.5 Na + , 1 Cl − , and GABA, moving 1.5 positive charges in the direction of GABA transport ( Voss et al, 2004 ).…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

et al. 2021

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SUMMARY Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

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Section: Resultsmentioning

confidence: 99%

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

et al. 2021

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“…Hepatic GABA transporters, Betaine GABA transporter 1 (BGT1) and GABA transporter 2 (GAT2), both co-transport 3 sodium ions and 1 chloride ion (19). To establish the role of these ion dependent transporters in GABA export we show that hepatic slice GABA release is encouraged by incubation in media with low concentrations of sodium and chloride ions ( Fig.…”

Section: Neurotransmitter Releasementioning

confidence: 95%

Hepatocyte Membrane Potential Regulates Serum Insulin and Insulin Sensitivity by Altering Hepatic GABA Release

Geisler

Ghimire

Hepler

et al. 2018

Preprint

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The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing and diet induced obesity increases hepatic GABA release in mice. Hepatic GABA release decreases hepatic afferent vagal nerve activity to stimulate pancreatic insulin release and decreases insulin sensitivity. Surgically eliminating the hepatic vagal nerve signaling, preventing hepatic GABA synthesis, or limiting hepatic GABA export ameliorates hyperinsulinemia and insulin resistance in diet-induced obese mice. This work establishes that limiting hepatocyte GABA production or release may mute the glucoregulatory dysfunction common to obesity. Transaminase, Aspartate CEG -Experimental design and project conceptualization, performed experiments and wet lab analyses, wrote initial draft of manuscript, generated figures, reviewed and edited manuscript. CH -Performed experiments and wet lab analyses, reviewed and edited manuscript. SG -Performed experiments and wet lab analyses, reviewed and edited manuscript. MRH -Developed electrophysiology methodology and performed experiments, reviewed manuscript. RFF -Developed electrophysiology methodology, reviewed and edited manuscript. BJR -Experimental design and project conceptualization, performed surgeries and experiments, analyzed statistics, reviewed and edited manuscript. Acknowledgments:The authors wish to thank Dr. Scott Sternson at the Howard Hughes Medical Institute, Ashburn, VA., for kindly providing the PSEM89S ligand used in these studies, Ken Pendarvis at the University of Arizona for analyzing aspartate release from our ex vivo hepatic slice culture model by liquid chromatography-mass spectrometry, The Mayo Clinic Metabolomics Regional Core for performing the initial mass spectrophotometry analysis of media from our ex vivo hepatic slice culture model using their neurotransmitter panel to identify potential hepatocyte released signaling molecules, and Drs. Masoud Ghamari-Langroudi and Richard Levine for guidance on experimental models and electrophysiology.

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“…SLC6A1 is found primarily in the synapse of presynaptic neurons, while SLC6A11 localizes to the cell membrane of astrocytes in close proximity to the synapses of GABAeric neurons [166,170]. The transport function of GABA transporters is driven by sodium and chloride cotransport, although the exact stoichiometry of this transport varies [170,171]. SLC6A13 is not only expressed in the brain but also in peripheral tissues like the liver and kidney [161].…”

Section: Slc6mentioning

confidence: 99%

A guide to plasma membrane solute carrier proteins

2020

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This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.

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Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters

Cited by 16 publications

References 176 publications

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Hepatocyte Membrane Potential Regulates Serum Insulin and Insulin Sensitivity by Altering Hepatic GABA Release

A guide to plasma membrane solute carrier proteins

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