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Review
. 2013 Dec 31:4:199.
doi: 10.3389/fendo.2013.00199.

The Amino Acid Transporters of the Glutamate/GABA-Glutamine Cycle and Their Impact on Insulin and Glucagon Secretion

Monica Jenstad  1 , Farrukh Abbas Chaudhry  2
Affiliations
Review

The Amino Acid Transporters of the Glutamate/GABA-Glutamine Cycle and Their Impact on Insulin and Glucagon Secretion

Monica Jenstad et al. Front Endocrinol (Lausanne). .

Abstract

Intercellular communication is pivotal in optimizing and synchronizing cellular responses to keep homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS), glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, CNS proteins involved in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA, and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters (Slc1, Slc17, Slc32, and Slc38) and physiology of hormone secretion in islets of Langerhans.

Keywords: GABA; SAT2; SN1; Slc38a2; Slc38a3; glutamate; glutamine; insulin.

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Figures

Figure 1
Figure 1
Amino acids in pancreatic endocrine signaling and insulin maturation. (A) Amino acids are shuttled between cells and intracellular compartments and are involved in autocrine and paracrine signaling in the pancreatic islets of Langerhans. High levels of glucose (Gluc) are carried by the blood flow to the islet β-cells where glucose is accumulated by a glucose transporter (GLUT2). Through glycolysis, glucose is catabolized to pyruvate (Pyr) which is transported into mitochondria for oxidative phosphorylation. The product, ATP, inhibits K+-channels. As a result, β-cells are depolarized and this stimulates fusion of insulin containing secretory granules (SGs) with the plasma membrane. Glutamine carried by blood can be accumulated inside β-cells by SN1 on their plasma membrane. Glutamine may be converted to glutamate by phosphate-activated glutaminase (PAG) and enter the TCA cycle inside mitochondria (1) to produce ATP which may regulate K+-channels in the same way as glucose. Alternatively, glutamate may be translocated into synaptic-like microvesicles (SLMVs) (3) or insulin containing SG (4). Finally, glutamate may be metabolized to GABA (2) by glutamic acid decarboxylase (GAD) and accumulated inside SLMVs for secretion. In α-cells, SAT2 accumulates high levels of glutamine which may be metabolized to glutamate and/or GABA by PAG and GAD, respectively. The vesicular glutamate transporters (VGLUT) 1 and 2 and VGAT then transport glutamate (1) and GABA (2) into SLMVs and glucagon containing SG for exocytotic release. (B) VGLUT3-mediated transport of glutamate into SGs, followed by GLT/EAAT2-mediated transport out, contributes to maturation of insulin. A vacuolar (V)-ATPase generates a high electrochemical gradient for H+. Flux of H+ through VGLUT3 and down its electrochemical gradient energizes transport of glutamate (Glu−) into SGs. Subsequently, the glutamate transporter GLT/EAAT2 translocates glutamate out of the SG, and this transport is coupled to 3 Na+ and 1 H+ transport in symport and 1 K+ in antiport. The concerted action of VGLUT3 and GLT/EAAT2 results in a net movement of positive charge out of the SG. This counteracts inhibition of the V-ATPase and augments accumulation of H+ inside SG. Such acidification stimulates conversion of pro-insulin to insulin. The chloride channel CLC-3 also resides on the membranes of SG. Transport of Cl− down its electrochemical gradient (into SG lumen) by CLC-3 also counteracts inhibition of the V-ATPase and increases the luminal acidification which stimulates maturation of insulin.
Figure 2
Figure 2
Direction of glutamine transport in the islet cells of Langerhans is differential and dependent on prandial status. (A) Postprandially, blood supplied to the islets is enriched in glucose and amino acids such as glutamine (Gln). Gln is captured by SN1 and metabolized in β-cells to stimulate insulin secretion as described (Figure 1). As a result, blood glucose levels are reduced. (B) Interprandially, blood supplied to the islets has lower concentrations of Gln and glucose. Gln now preferentially activates SAT2 on α-cells due to its higher affinity for Gln. In addition, changes in the Gln gradient across the cell membrane of β-cells may stimulate SN1 to release glutamine which can then be taken up by adjacent α-cells. Enhanced Gln metabolism in α-cells stimulates secretion of glucagon which raises blood glucose levels.
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