Glycine Binding Site of the Synaptic NMDA Receptor in Subpostremal NTS Neurons

Baptista, Vander; Varanda, Wamberto Antônio

doi:10.1152/jn.00927.2004

Cited by 22 publications

(12 citation statements)

References 38 publications

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“…1c,d). The classical NMDA receptors comprised of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits require co-agonism of their subunit binding sites for activation25303132. Since GluN1 is an obligatory subunit31 and full agonism at the glycine site is necessary for full NMDA receptor activation33, we tested the gluco-regulatory ability of DVC ALX infusion when GluN1 is inactivated.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

et al. 2016

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Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.

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Section: Resultsmentioning

confidence: 99%

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

et al. 2016

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“…This is likely due to the activity of high capacity glycine transporters 1 and 2 that maintain low glycine concentrations at synaptic clefts proximal to NMDA receptors in the DVC. 36,37 Of note, although it remains to be assessed whether the activation of the NR2 subunit of the NMDA receptors in the DVC lowers VLDL-TG, it is unlikely that the nonconventional NMDA receptors that are comprised of NR1 and NR3 subunits (which are resistant to MK-801 35,38 ) are involved since DVC MK-801 negated the hypolipidemic effect of glycine.…”

Section: Discussionmentioning

confidence: 99%

Glycine Normalizes Hepatic Triglyceride-Rich VLDL Secretion by Triggering the CNS in High-Fat Fed Rats

Yue

Mighiu²,

Naples³

et al. 2012

Circulation Research

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Rationale: Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesityand type 2 diabetes contributes to the dyslipidemia that leads to cardiovascular morbidity. The central nervous system (CNS), particularly the hypothalamus, regulates hepatic lipid metabolism. Although the underlying neurocircuitry remains elusive, glycine has been documented to enhance CNS N-methyl-D-aspartate (NMDA) receptor-mediated transmission.Objective: We tested the hypothesis that glycine regulates hepatic VLDL-TG secretion by potentiating NMDA receptor-mediated transmission in the CNS. Methods and Results:Using 10-hour fasted male Sprague-Dawley rats implanted with stereotaxic cannulae into an extrahypothalamic region termed the dorsal vagal complex (DVC) and vascular catheters to enable direct DVC infusion and blood sampling, respectively, the rate of hepatic VLDL-TG secretion was measured following tyloxapol (an inhibitor of lipoprotein lipase) injection. Direct DVC infusion of glycine lowered VLDL-TG secretion, whereas NMDA receptor blocker MK-801 fully negated glycine's effect. NR1 subunit of NMDA receptor antagonist 7-chlorokynurenic acid, adenoviral injection of NR1 short hairpin RNA (shRNA), and hepatic vagotomy also nullified glycine's effect. Finally, DVC glycine normalized the hypersecretion of VLDL-TG induced by high-fat feeding. Key Words: glycine Ⅲ NMDA receptors Ⅲ CNS Ⅲ hepatic lipid metabolism Ⅲ obesity H ypertriglyceridemia and overproduction and secretion of VLDL-TG are key contributors to the metabolic syndrome and atherogenic dyslipidemia. 1-3 Although circulating insulin and free fatty acids (FFA) regulate hepatic VLDL-TG secretion, 4,5 the underlying regulatory mechanisms remain unclear. Given that diabetes and obesity are associated with hypertriglyceridemia and increased hepatic secretion and production of VLDL-TG, 1-3 it is important to elucidate the regulatory mechanisms of hepatic VLDL-TG secretion in a normal setting with the hope to discover novel therapeutic molecules to lower blood lipid levels in obesity and diabetes. Conclusions:In addition to the array of circulating factors that directly regulate hepatic lipid metabolism, the hypothalamic region of the brain senses circulating nutrients and hormones to regulate peripheral lipid homeostasis 6 -10 and blood pressure. 11 For example, nutrients such as glucose signal within the hypothalamus to inhibit VLDL-TG secretion through the hepatic vagus. 12 Consistent with the fact that nutrients in the brain lowers appetite through the suppression of neuropeptide Y, 13 direct administration of neuropeptide Y into the hypothalamus conversely stimulates VLDL-TG secretion. 9 Central neuropeptide Y signaling also negates the ability of circulating insulin to inhibit VLDL-TG secretion, 6 whereas hormones such as insulin, 8 ghrelin, 7 melanocortins, 14,15 and leptin 16,17 trigger hypothalamic signaling cascades to modulate peripheral lipid profiles. In spite of the fact that the hypothalamus regulates peripheral lipid metabolism, ...

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“…One possible explanation for a lack of ability of DVC NR1 inhibition alone to increase glucose production and induce hyperglycemia is that the glycine binding site is unsaturated at basal conditions (34). This is supported by the fact that glycine concentration at the DVC glutamatergic synapses is lower than CSF glycine concentration because of the presence of local high-capacity glycine transporters (34). Thus, DVC NMDA receptors in resting basal conditions are not sufficiently activated to lower glucose production.…”

Section: Discussionmentioning

confidence: 99%

Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production

Lam

Chari

et al. 2010

Journal of Biological Chemistry

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Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity.Diabetes and obesity are partly characterized by a disruption in glucose homeostasis. An elevation of glucose production and/or a decrease in glucose uptake lead to a rise in plasma glucose levels and the breakdown of gluco-regulatory homeostatic mechanisms. In fact, an increased production of glucose by the liver is determined to be the major contributing factor to fasting hyperglycemia in type 2 diabetes (1).To date, the mechanisms underlying the regulation of hepatic glucose production and homeostasis in healthy and obese/diabetic conditions remain to be elucidated. In this regard, the hypothalamus detects a rise in nutrients and hormones to regulate peripheral glucose homeostasis and specifically lower glucose production (2-14). However, the neuronal network that controls glucose homeostasis remains unclear.The N-methyl-D-aspartate (NMDA) 5 receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively (15). NMDA is a selective agonist of NMDA receptors and NMDA receptors are fundamental to excitatory neurotransmission (Fig. 1a). In the CNS, the NMDA receptors have important roles in synaptic plasticity and neuronal development (16). In addition, direct administration of NMDA receptor blocker into the DVC negates the ability of lipid/cholecystokinin-sensing mechanisms in the gut to regulate glucose production (17, 18). However, it remains unknown whether direct a...

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Glycine Binding Site of the Synaptic NMDA Receptor in Subpostremal NTS Neurons

Cited by 22 publications

References 38 publications

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

Glycine Normalizes Hepatic Triglyceride-Rich VLDL Secretion by Triggering the CNS in High-Fat Fed Rats

Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production

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