The Glutamate Agonist Homocysteine Sulfinic Acid Stimulates Glucose Uptake through the Calcium-dependent AMPK-p38 MAPK-Protein Kinase C ζ Pathway in Skeletal Muscle Cells

Abstract

Homocysteine sulfinic acid (HCSA) is a homologue of the amino acid cysteine and a selective metabotropic glutamate receptor (mGluR) agonist. However, the metabolic role of HCSA is poorly understood. In this study, we showed that HCSA and glutamate stimulated glucose uptake in C2C12 mouse myoblast cells and increased AMP-activated protein kinase ( Homocysteine, a sulfur-containing amino acid, is a potent and selective metabotropic glutamate receptor agonist (1). A number of epidemiologic studies have shown that moderate hyperhomocysteinemia is a risk factor for atherosclerosis (2, 3), stroke (4), Alzheimer disease (5), and schizophrenia (6). Hyperhomocysteinemia is common in patients with non-insulin-dependent diabetes mellitus (7) and nephritic diabetes (8), suggesting a possible relationship between homocysteine and the pathogenesis. Recent evidence has indicated the presence of glutamate receptors in non-neuronal tissues, including skeletal muscle cells; however, the functional implications involving homocysteine in diabetes are not fully understood.AMP-activated protein kinase (AMPK) 2 is a phylogenetically conserved intracellular energy sensor that plays a central role in the regulation of glucose and lipid metabolism. AMPK, a heterotrimeric complex composed of a catalytic subunit and two regulatory subunits, is activated when cellular energy is depleted (9). Upon activation by allosteric binding of AMP or phosphorylation at Thr 172 of the catalytic subunit by AMPK kinase, AMPK accelerates ATP-generating catabolic pathways, including glucose and fatty acid oxidation (10 -12), while simultaneously reducing ATP-consuming anabolic pathways, including cholesterol, fatty acid, and triacylglycerol synthesis (13).Some nonessential amino acids and derivatives, such as L-glutamate, L-aspartate, and ␥-aminobutyric acid, have long been known to act as neurotransmitters (14). In addition, a group of sulfur-containing amino acids has previously been shown to exhibit effects similar to those of L-glutamic acid and L-aspartic acid (15). Glutamate is the most prominent and excitatory neurotransmitter at the neuromuscular junction. Glutamate receptors can be subdivided into two classes: ionotropic and metabotropic. Ionotropic glutamate receptors are ligand-gated, nonselective cation channels that allow the flow of Na

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

“…5f) that lack LKB1 (refs 49, 50). Therefore, we tested the impact of CaMKKβ, another kinase for AMPK15, which had been shown in an earlier study to mediate AMPK phosphorylation in response to the glutamate agonist homocysteine sulfinic acid45. We found indeed that CaMKKβ inhibition prevented AMPK activation by aa.…”

“…This suggests aa as novel metabolic activators of AMPK. This finding was unexpected because AMPK is mainly considered to be activated by stress and starvation conditions, including aa withdrawal44 although there is conflicting data45. This may in turn imply that aa exert an inhibitory effect on AMPK, which has indeed been suggested by several studies464748.…”

Orally Active Osteoanabolic Agent GTDF Binds to Adiponectin Receptors, With a Preference for AdipoR1, Induces Adiponectin-Associated Signaling, and Improves Metabolic Health in a Rodent Model of Diabetes

“…Apart from adiponectin, glutamate receptors also activate AMPK and p38 (26), and we therefore assessed if GTDF could modulate these receptors. However, GTDF failed to bind to or activate/repress any of the ionotropic or metabotropic glutamate receptors (mGlu), whereas quercetin strongly activated mGlu2 and inhibited mGlu4, -6, and -8 ( Supplementary Tables 1 and 2).…”

Holistic and dynamic metabolic alterations of traditional Chinese medicine syndrome in a toxic heat and blood stasis syndrome rat model

“…Then 6 mL blood obtained with the heart puncture technique was collected into one 2 mL sodium citrate vacuum blood collection tube (SCVBCT) and two 2 mL EDTA vacuum blood collection tubes (EVBCTs). The blood sample in one of the EVBCTs stood at room temperature (22)(23)(24)(25) C) for 30 min. The blood samples in the SCVBCT and the other EVBCT were centrifuged at 3000 rpm for 10 min to get the plasma and stored at À80 C until the biochemical analysis.…”

“…Prior to UPLC-MS analysis, the urine samples were thawed at room temperature (22)(23)(24)(25) C), diluted at a ratio of 2 : 1 (v/v) using ultra high purity water, vortex mixed and centrifuged at 14 000 rpm for 10 min at 4 C.…”