Rat Brain Creatine Kinase Messenger RNA Levels Are High in Primary Cultures of Brain Astrocytes and Oligodendrocytes and Low in Neurons

Molloy, George R.; Wilson, Charlie D.; Benfield, Pamela A.; deVellis, Jean; Kumar, Sumit

doi:10.1111/j.1471-4159.1992.tb11028.x

Cited by 49 publications

(72 citation statements)

References 37 publications

(25 reference statements)

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“…In the mouse cerebral cortex, uMt-CK is expressed selectively in excitatory and inhibitory neurons, and localized in their mitochondria in dendrites, cell bodies, axons and terminals [17]. In primary cultures of rat astrocytes, the BB-CK mRNA level is up to 15 times higher than in neurons [18]. In the adult brain, the strongest uMt-CK expression is reported in neurons from layer Va pyramidal cells, thalamic nuclei, cerebellar Purkinje cells, olfactory mitral cells and hippocampal interneurons [19].…”

Section: Discussionmentioning

confidence: 99%

Impaired Brain Creatine Kinase Activity in Huntington’s Disease

et al. 2010

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Background: Huntington’s disease (HD) is associated with impaired energy metabolism in the brain. Creatine kinase (CK) catalyzes ATP-dependent phosphorylation of creatine (Cr) into phosphocreatine (PCr), thereby serving as readily available high-capacity spatial and temporal ATP buffering. Objective: Substantial evidence supports a specific role of the Cr/PCr system in neurodegenerative diseases. In the brain, the Cr/PCr ATP-buffering system is established by a concerted operation of the brain-specific cytosolic enzyme BB-CK and ubiquitous mitochondrial uMt-CK. It is not yet established whether the activity of these CK isoenzymes is impaired in HD. Methods: We measured PCr, Cr, ATP and ADP in brain extracts of 3 mouse models of HD – R6/2 mice, N171-82Q and HdhQ¹¹¹ mice – and the activity of CK in cytosolic and mitochondrial brain fractions from the same mice. Results: The PCr was significantly increased in mouse HD brain extracts as compared to nontransgenic littermates. We also found an approximately 27% decrease in CK activity in both cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice, and an approximately 25% decrease in the mitochondria from HdhQ¹¹¹ mice. Moreover, uMt-CK and BB-CK activities were approximately 63% lower in HD human brain samples as compared to nondiseased controls. Conclusion: Our findings lend strong support to the role of impaired energy metabolism in HD, and point out the potential importance of impairment of the CK-catalyzed ATP-buffering system in the etiology of HD.

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Section: Discussionmentioning

confidence: 99%

Impaired Brain Creatine Kinase Activity in Huntington’s Disease

et al. 2010

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“…Located in the cytoplasm of glial cells 38 and GABAergic interneurons, 39 CKB reversibly catalyses the transfer of phosphate between ATP and various phosphogens such as creatine phosphate, 40 important in the brain for habituation, spatial learning and behaviour. 41 Cells with high CKB expression are known to be resistant to neurological insults, such as glucose and oxygen deprivation 39 and as such the increased CKB expression in the ACC gray matter may protect cells from oxidative damage observed in the disease state.…”

Section: Metabolismmentioning

confidence: 99%

“…However, activity of CKB is thought to be reduced in the frontal cortex, anterior and posterior cingulate, hippocampus and cerebellum in schizophrenia. 42 These conflicting data may be due to the location of CKB to subsets of cells 38,39 which are differentially affected in schizophrenia. CK-Mit, located on the membrane of neurons is involved in the generation of ATP 43 and possibly glutamate filling into synaptic vesicles.…”

Section: Metabolismmentioning

confidence: 99%

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

et al. 2006

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The Anterior Cingulate Cortex (ACC, Brodmans Area 24) is implicated in the pathogenesis of schizophrenia due to its normal functions and connectivity together with reports of structural, morphological and neurotransmitter aberrations within this brain area in the disease state. Two-dimensional gel electrophoresis (2DE) was employed to scan and compare the ACC gray matter proteomes between schizophrenia (n = 10) and control (n = 10) post-mortem human tissue. This proteomic approach has detected 42 protein spots with altered levels in the schizophrenia cohort, which to our knowledge is the first proteomic analysis of the ACC in schizophrenia. Thirty nine of these proteins were subsequently identified using mass spectrometry and functionally classified into metabolism and oxidative stress, cytoskeletal, synaptic, signalling, trafficking and glial-specific groups. Some of the identified proteins have previously been implicated in the disease pathogenesis and some offer new insights into schizophrenia. Investigating these proteins, the genes encoding these proteins, their functions and interactions may shed light on the molecular mechanisms underlying the heterogeneous symptoms characteristic of schizophrenia.

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“…Expression of rat CKB mRNA, however, is more widespread, being highest in astrocytes and oligodendrocytes in the brain (36), much lower in cardiac muscle and kidney, and barely detectable in some other tissues (e.g., liver) (23,35,54). The molecular basis of CKB regulation in different cell types is not completely understood.…”

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confidence: 99%

Mouse p53 represses the rat brain creatine kinase gene but activates the rat muscle creatine kinase gene.

et al. 1994

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The creatine kinases (CK) regenerate ATP for cellular reactions with a high energy expenditure. While muscle CK (CKM) is expressed almost exclusively in adult skeletal and cardiac muscle, brain CK (CKB) expression is more widespread and is highest in brain glial cells. CKB expression is also high in human lung tumor cells, many of which contain mutations in p53 alleles. We bp -195 to +5 of the CKB promoter and within bp -168 to -97 of the CKM promoter. Moreover, a 112-bp fragment from the proximal rat CKM promoter (bp -168 to -57), which contained five degenerate p53-binding elements, was capable of conferring p53-mediated activation on a heterologous promoter in CV-1 cells. Also, this novel p53 sequence, when situated in the native 168-bp rat CKM promoter, conferred p53-mediated activation equal to or greater than that of the originally characterized far-upstream (bp -3160) mouse CKM p53 element. Therefore, CKB and CKM may be among the few cellular genes which could be targets of p53 in vivo. In addition, we analyzed a series of missense mutants with alterations in conserved region II of p53. Mutations affected p53 transrepression and transactivation activities differently, indicating that these activities in p53 are separable. The ability of p53 mutants to transactivate correlated well with their ability to inhibit transformation of rat embryonic fibroblasts by adenovirus Ela and activated Ras.The creatine kinases (CKs) (EC 2.7.3.2) catalyze the reversible transfer of a high-energy phosphate group from creatine phosphate to ADP, thus regenerating ATP in cellular reactions which expend large amounts of ATP, e.g., muscle contraction and ion transport (55). Vertebrates express four distinct CK enzymes which are products of separate, single-copy genes: the brain isoform (CKB), the muscle isoform (CKM), and two mitochondrial isoforms (CKmi). The active form of the cytoplasmic CK is a dimer which exists in three, electrophoretically separable isoforms: MM (predominant form in adult skeletal and cardiac muscle), BB (predominant form in the brain and embryonic skeletal and cardiac muscle), and MB (present in embryonic and cardiac muscle in moderate amounts) (55). The CKmi self-associates to form dimers and octamers located on the outer surface of the inner mitochondrial membrane (55). It has been proposed that the ATP generated in the mitochondrion is used (by CKmi) to generate creatine phosphate, which is subsequently transported to the cytoplasm and used by the cytoplasmic CK (CKB or CKM) to regenerate ATP at sites of high ATP consumption (55).Transcription of CKM is regulated in a highly tissue specific manner, being expressed almost exclusively in skeletal and cardiac muscle (23,24,35,54). In undifferentiated dividing myoblasts, CKM is not expressed and CKB is barely detectable. Early after myoblast fusion, CKB mRNA is transiently expressed and then returns to basal levels, at which time * Corresponding author. Phone: (302) 831-2281. expression of CKM mRNA begins and increases thereafter to allow CKM t...

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Rat Brain Creatine Kinase Messenger RNA Levels Are High in Primary Cultures of Brain Astrocytes and Oligodendrocytes and Low in Neurons

Cited by 49 publications

References 37 publications

Impaired Brain Creatine Kinase Activity in Huntington’s Disease

Impaired Brain Creatine Kinase Activity in Huntington’s Disease

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

Mouse p53 represses the rat brain creatine kinase gene but activates the rat muscle creatine kinase gene.

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