Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis

Eur J Neurosci. 2004 Jul;20(1):144-60. doi: 10.1111/j.1460-9568.2004.03478.x.


The creatine/phosphocreatine shuttle system, as catalysed reversibly by creatine kinases, is thought to be essential for the storing and buffering of high phosphate-bound energy in tissues with high energy demand. In the present study, we aimed to clarify the cellular system of creatine biosynthesis and its energy metabolism in the mouse brain by immunohistochemistry for creatine biosynthetic enzyme S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT), ubiquitous mitochondrial creatine kinase (uCK-Mi) and brain-type cytoplasmic creatine kinase (CK-B). GAMT was expressed highly in oligodendrocytes and olfactory ensheathing glia and moderately in astrocytes, whereas GAMT was very low in neurons and microglia. By contrast, uCK-Mi was expressed selectively in neurons and localized in their mitochondria in dendrites, cell bodies, axons and terminals. The distinct and almost complementary distribution of GAMT and uCK-Mi suggests that the creatine in neuronal mitochondria is derived not only from the circulation, but also from local glial cells associated with these neuronal elements. By contrast, CK-B was selective to astrocytes among glial populations, and was exclusive to inhibitory neurons among neuronal populations. Interestingly, these cells with high CK-B immunoreactivity are known to be highly resistant to acute energy loss, such as hypoxia and hypoglycemia. Considering that phosphocreatine generates ATP much faster than the processes of glycolysis and oxidative phosphorylation, the highly regulated cellular expressions of creatine biosynthetic and metabolic enzymes suggest that the creatine/phosphocreatine shuttle system plays a role in brain energy homeostasis through a novel neuron-glial relationship.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Brain / enzymology*
  • Brain / metabolism
  • Brain / ultrastructure
  • Calbindins
  • Carrier Proteins / metabolism
  • Creatine Kinase / metabolism*
  • Creatine Kinase, BB Form
  • Creatine Kinase, Mitochondrial Form
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Glial Fibrillary Acidic Protein / metabolism
  • Glucose Transporter Type 1
  • Guanidinoacetate N-Methyltransferase
  • Homeostasis / physiology
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • Isoenzymes / metabolism*
  • Membrane Transport Proteins / metabolism
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Immunoelectron / methods
  • Microtubule-Associated Proteins / metabolism
  • Monosaccharide Transport Proteins / metabolism
  • Myelin Proteolipid Protein / genetics
  • Myelin Proteolipid Protein / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / enzymology*
  • Neuroglia / metabolism
  • Neuroglia / ultrastructure
  • Neurons / enzymology*
  • Neurons / metabolism
  • Neurons / ultrastructure
  • S100 Calcium Binding Protein G / metabolism
  • Thymosin / metabolism


  • Calbindins
  • Carrier Proteins
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • Glucose Transporter Type 1
  • Isoenzymes
  • Membrane Transport Proteins
  • Microtubule-Associated Proteins
  • Monosaccharide Transport Proteins
  • Myelin Proteolipid Protein
  • Nerve Tissue Proteins
  • S100 Calcium Binding Protein G
  • creatine transporter
  • thymosin beta(4)
  • Thymosin
  • Methyltransferases
  • S-adenosyl methionine thioether S-methyltransferase
  • Gamt protein, mouse
  • Guanidinoacetate N-Methyltransferase
  • Creatine Kinase
  • Creatine Kinase, BB Form
  • Creatine Kinase, Mitochondrial Form