ABSTRACT
Four cases of autosomal dominant CNS disorders related to CACNA1A mutations and detected by massive parallel sequencing are reported: a non-familial case of episodic ataxia type 2 (EA2) with the previously reported mutation c.269_270insA (p.Tyr90Ter) in a 35-year-old man; familial hemiplegic migraine type 1 (FHM1) in a girl aged 3 years 10 months and her mother aged 38 yrs with a novel mutation 1829C>T (p.Ser610Phe), members of a family with 4 patients and incomplete penetrance; developmental and epileptic encephalopathy 42 (DEE42) in a 9-year-old girl and a 5-year-old boy from different families with the identical de novo mutation c.2137G>A (p.Ala713Thr) reported earlier. Clinical and genetic characteristics are analyzed compared to literature.
Subject(s)
Calcium Channels , Migraine with Aura , Adult , Calcium Channels/genetics , Child , Child, Preschool , Female , Humans , Male , Mutation , PedigreeABSTRACT
In this review, we discuss the role of glutamine in the nervous system as a precursor of the excitatory neuromediator glutamate, on one hand, and as an energy substrate for mitochondria in nerve and glial cells during normal and pathological processes, on the other hand. Particular attention is devoted to the functioning of the glutamine-glutamate cycle enzymes during brain ischemia and hypoglycemia and to processes of neuromediator regeneration in neurons. We thoroughly discuss the role of glutamine synthetase in mechanisms of ammonium detoxification and the role of glutamine as a possible factor in astrocyte damage. The analyzed data suggest that the constant maintenance of optimal concentrations and ratio of glutamine to glutamate in nerve tissue is not only critically important for the normal functioning of nervous system, but is also necessary for neuron and astrocyte viability.
Subject(s)
Brain Ischemia , Glutamic Acid/metabolism , Hypoglycemia , Neurons/metabolism , Animals , Brain Ischemia/metabolism , Brain Ischemia/pathology , Brain Ischemia/physiopathology , Cell Death , Cell Survival , Humans , Hypoglycemia/metabolism , Hypoglycemia/pathology , Hypoglycemia/physiopathology , Neurons/pathologyABSTRACT
The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival.
Subject(s)
Glutamine/physiology , Mitochondria/physiology , Neurons/physiology , Animals , Calcium/metabolism , Cations, Divalent , Cell Death , Cells, Cultured , Cerebellum/cytology , Electron Transport Complex I/antagonists & inhibitors , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glucose/deficiency , Glutamine/pharmacology , Intracellular Space/metabolism , Membrane Potential, Mitochondrial , Mitochondria/drug effects , N-Methylaspartate/pharmacology , Neurons/cytology , Neurons/drug effects , Ouabain/pharmacology , Rats , Rats, Wistar , Rotenone/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitorsABSTRACT
This review collects data on the influence of intracellular and extracellular acidosis on neuronal viability and the effect of acidosis on neuronal damage progressing under brain ischemia/hypoxia. Particular attention is devoted to the involvement of ionotropic glutamic receptors and acid-sensitive ion channel 1a in these processes.
