Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport

Buck, Charles R.; Jurynec, Michael J.; Dk, Gupta; Law, Alick K T; Bilger, Johannes; Wallace, Douglas C.; McKeon, Robert J.

doi:10.1016/s0014-4886(03)00043-8

Cited by 25 publications

(27 citation statements)

References 49 publications

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“…Previously, we observed that Ant1 is up-regulated in response to cortical lesions resulting in glial scaring [26] and that this is mediated through TGFβ-Smad signal transduction pathway [27]. To determine if Ant1 is also inducible in neurons, we used Western blots to examine the levels of Ant1 and Ant2 in culture hippocampal neurons, following 24h exposure to 100 µM glutamate.…”

Section: Resultsmentioning

confidence: 99%

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Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults

Lee¹,

Schriner²,

Wallace³

2009

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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The mitochondrial adenine nucleotide translocators (Ant) are bi-functional proteins that transport ADP and ATP across the mitochondrial inner membrane, and regulate the mitochondrial permeability transition pore (mtPTP) which initiates apoptosis. The mouse has three Ant isoforms: Ant1 expressed in heart, muscle, and brain; Ant2 expressed in all tissues but muscle; and Ant4 expressed primarily in testis. Ant1-deficient mice manifest muscle and heart but not brain pathology. Brain Ant1 is induced by stress, while Ant2 is not. Ant1-deficient mice are resistant to death induced by systemic exposure to the brain excitotoxin, kainic acid (KA), and their hippocampal and cortical neurons are significantly more resistant to neuronal death induced by glutamate, KA, and etoposide‥ The mitochondrial membrane potential of Ant1-deficient brain mitochondria is increased and the mtPTP is more resistance to Ca++ induced permeability transition. Hence, Ant1-deficiency may protect the brain from excitotoxicity by desensitizing the mtPTP and by blocking the pro-apoptotic induction of Ant1 by stress.

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Section: Resultsmentioning

confidence: 99%

“…We have previously shown that Ant1, but not Ant2, is induced by brain trauma, medicated by TGFβ and the Smad pathway [26, 27]. Furthermore, it has been reported that increased expression of Ant1 achieved by transfection of cultured cells is pro-apoptotic [37].…”

Section: Discussionmentioning

confidence: 99%

Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults

Lee¹,

Schriner²,

Wallace³

2009

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…Conversely up-regulation of ANT1 in reactive astrocytes is associated with increased glutamate uptake. This effect seemed rather selective, as deletion of ANT1 did not alter other energy using processes, such as proliferation (Buck et al, 2003). In some studies, inhibition of mitochondrial function alone with inhibitors or by removing oxygen has no effect on glutamate uptake.…”

Section: Coupling Of Glutamate Transport To Mitochondriamentioning

confidence: 99%

Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

Robinson

Jackson

2016

Neurochemistry International

137

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In the mammalian brain, a family of sodium-dependent transporters maintains low extracellular glutamate and shapes excitatory signaling. The bulk of this activity is mediated by the astroglial glutamate transporters GLT-1 and GLAST (also called EAAT2 and EAAT1). In this review, we will discuss evidence that these transporters co-localize with, form physical (co-immunoprecipitable) interactions with, and functionally couple to various ‘energy-generating’ systems, including the Na+/K+-ATPase, the Na+/Ca2+ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins. This functional coupling is bidirectional with many of these systems both being regulated by glutamate transport and providing the ‘fuel’ to support glutamate uptake. Given the importance of glutamate uptake to maintaining synaptic signaling and preventing excitotoxicity, it should not be surprising that some of these systems appear to ‘redundantly’ support the energetic costs of glutamate uptake. Although the glutamate-glutamine cycle contributes to recycling of neurotransmitter pools of glutamate, this is an over-simplification. The ramifications of co-compartmentalization of glutamate transporters with mitochondria for glutamate metabolism are discussed. Energy consumption in the brain accounts for ~20% of the basal metabolic rate and relies almost exclusively on glucose for the production of ATP. However, the brain does not possess substantial reserves of glucose or other fuels. To ensure adequate energetic supply, increases in neuronal activity are matched by increases in cerebral blood flow via a process known as ‘neurovascular coupling’. While the mechanisms for this coupling are not completely resolved, it is generally agreed that astrocytes, with processes that extend to synapses and endfeet that surround blood vessels, mediate at least some of the signal that causes vasodilation. Several studies have shown that either genetic deletion or pharmacologic inhibition of glutamate transport impairs neurovascular coupling. Together these studies strongly suggest that glutamate transport not only coordinates excitatory signaling, but also plays a pivotal role in regulating brain energetics.

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“…The Glt-Gln cycle between neurons and astrocytes is a major metabolic pathway requiring B80% of the total brain glucose consumption Shen et al, 1999). Astrocytic glucose utilization increase in response to rising interstitial Glt levels and astrocytic Glt uptake decrease when ATP production fails (Buck et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Cerebral Glutamine and Glutamate Levels in Relation to Compromised Energy Metabolism: A Microdialysis Study in Subarachnoid Hemorrhage Patients

Samuelsson

Hillered

Zetterling

et al. 2007

J Cereb Blood Flow Metab

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Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt-Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. Using microdialysis (MD) measurements from visually noninjured cortex in 33 neurointensive care patients with subarachnoid hemorrhage, we have determined how interstitial Glt and Gln, as a reflection of the Glt-Gln cycle turnover, relate to perturbed energy metabolism. A total of 3703 hourly samples were analyzed. The lactate/pyruvate (L/P) ratios correlated to the Gln/Glt ratios (r = À0.66), but this correlation was not stronger than the correlation between L/P and Glt (r = 0.68) or the correlation between lactate and Glt (r = 0.65). A novel observation was a linear relationship between interstitial pyruvate and Gln (r = 0.52). There were 13 periods (404 h) of 'energy crisis', defined by L/P ratios above 40. All were associated with high interstitial Glt levels. Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt-Gln cycling in the brain.

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Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport

Cited by 25 publications

References 49 publications

Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults

Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults

Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

Cerebral Glutamine and Glutamate Levels in Relation to Compromised Energy Metabolism: A Microdialysis Study in Subarachnoid Hemorrhage Patients

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