Removal of potential phosphorylation sites does not alter creatine transporter response to PKC or substrate availability

Lucia Santacruz, Marcus D. Darrabie, Rajashree Mishra, Danny O. Jacobs

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Creatine, Phosphocreatine, and creatine kinases, constitute an energy shuttle that links ATP production in mitochondria with cellular consumption sites. Myocytes and neurons cannot synthesize creatine and depend on uptake across the cell membrane by a specialized transporter to maintain intracellular creatine levels. Although recent studies have improved our understanding of creatine transport in cardiomyocytes, the structural elements underlying the creatine transporter protein regulation and the relevant intracellular signaling processes are unknown. Methods: The effects of pharmacological activation of kinases or phosphatases on creatine transport in cardiomyocytes in culture were evaluated. Putative phosphorylation sites in the creatine transporter protein were identified by bioinformatics analyses, and ablated using site-directed mutagenesis. Mutant transporter function and their responses to pharmacological PKC activation or changes in creatine availability in the extracellular environment, were evaluated. Results: PKC activation decreases creatine transport in cardiomyocytes in culture. Elimination of high probability potential phosphorylation sites did not abrogate responses to PKC activation or substrate availability. Conclusion: Modulation of creatine transport in cardiomyocytes is a complex process where phosphorylation at predicted sites in the creatine transporter protein does not significantly alter activity. Instead, nonclassical structural elements in the creatine transporter and/or interactions with regulatory subunits may modulate its activity.

Original languageEnglish (US)
Pages (from-to)353-360
Number of pages8
JournalCellular Physiology and Biochemistry
Issue number1
StatePublished - Aug 12 2015
Externally publishedYes


  • Cardiac metabolism
  • Creatine
  • Energy metabolism
  • Membrane transport
  • Phosphorylation
  • Protein kinase C (PKC)

ASJC Scopus subject areas

  • Physiology


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