Functional Maturation of Creatine Kinase in Rat Brain

Abstract

The physiological role of the phosphocreatine (PCr)/creatine kinase (CK) system has been studied in rat brain by comparing maturational changes in in vivo CK-catalyzed reaction rate and activities of CK isoenzymes. The CK-catalyzed reaction rates, measured by ³¹P-nuclear magnetic resonance spectroscopy, increased 4-fold between 12 and 17 days of age. The mitochondrial CK (Mi-CK) isoenzyme, as a percentage of total CK, increased to the same extent over this relatively narrow age period. Cytosolic CK (B-CK) was active earlier and, with the total CK activity, increased steadily over a longer time course. An immunohistochemical study of cerebellum showed Mi-CK predominantly in gray matter, while the cytosolic CK was present in rather large concentrations in both gray and white matter. In the molecular layer, B-CK was most prominent in the Bergmann glial cells, while Mi-CK was more prominent in Purkinje neurons. During development a redistribution of Mi-CK from the Purkinje cell bodies to their processes was observed. These results point to regional differences in CK content and in isoenzyme-specific localizations. The increase in CK activity is temporally coincident with the maturational appearance of closely coupled decreases in brain PCr and ATP during hypoxia. These maturational changes suggest that the activity of the PCr/CK system, particularly the Mi-CK isoenzyme, is central in regulation of brain ATP.

Brain Creatine Kinase and Creatine Transporter Proteins in Normal and Creatine-Treated Rabbit Pups

“…Turnover of ATP in gray matter is higher and more variable than in white matter. The creatine (Cr)/creatine kinase (CK)/phosphocreatine (PCr) system is closely coupled to ATP metabolism and shows similar regional heterogeneity in brain [4,5]. CK (EC 2.7.3.2) catalyzes the reversible transfer of phosphoryl groups between PCr and ATP (Cr + ATP ←→ F4 PCr + ADP + H + ).…”

“…The CrT facilitates the movement of Cr across the plasma membrane against a concentration gradient via a sodium-and chloride-dependent, high-affinity uptake process [9]. Piglet and rabbit brains show higher PCr concentration, and lower Mi-CK activity and Cr content in white matter compared to gray matter [4,5,10,11]. Developmentally, brain PCr/nucleoside triphosphate (NTP) ratio increases between 5 and 25 postnatal days in rat and between 5 and 30 days in rabbit, probably due to increased PCr in both species [12][13][14][15].…”

Brain ATP Metabolism in Hypoxia Resistant Mice Fed Guanidinopropionic Acid

“…The variation in specific metabolic adaptations apparent in different tissues suggests specific differences in regulation of enzymes of ATP and ADP metabolism and in the physiology of the CK reaction (table 5). This variation in adaptive responses is also seen in cerebral grey matter and white matter, in which there are different rates of ATP metabolism, CK reactant concentrations, and isoenzyme activities [9,10,17]. Changes in ATP metabolism suggest that the CK system plays a central role in the physiology of brain cellular energy metabolism.…”

“…3 Estimated from total CK and mitochondrial CK. 4 Taken from O'Gorman et al, 1996 [7] and based on the assumption that all mitochondrial CK is in grey matter [10].…”

“…These observations suggest that GPA replaces creatine in a cerebral compartment in which the CK reaction rate is high and into which creatine is transported rather than synthesized [8]. Recent studies suggest that this compartment may be white matter, which has a rapid CK reaction rate, low mitochondrial CK versus cytosolic B-CK, a high phosphocreatine:NTP ratio, and slower and more stable ATP turnover compared to grey matter [9,10].…”