Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism

J Biol Chem. 2015 Sep 25;290(39):23751-65. doi: 10.1074/jbc.M115.643544. Epub 2015 Aug 5.


Ca(2+) permeation and/or binding to the skeletal muscle L-type Ca(2+) channel (CaV1.1) facilitates activation of Ca(2+)/calmodulin kinase type II (CaMKII) and Ca(2+) store refilling to reduce muscle fatigue and atrophy (Lee, C. S., Dagnino-Acosta, A., Yarotskyy, V., Hanna, A., Lyfenko, A., Knoblauch, M., Georgiou, D. K., Poché, R. A., Swank, M. W., Long, C., Ismailov, I. I., Lanner, J., Tran, T., Dong, K., Rodney, G. G., Dickinson, M. E., Beeton, C., Zhang, P., Dirksen, R. T., and Hamilton, S. L. (2015) Skelet. Muscle 5, 4). Mice with a mutation (E1014K) in the Cacna1s (α1 subunit of CaV1.1) gene that abolishes Ca(2+) binding within the CaV1.1 pore gain more body weight and fat on a chow diet than control mice, without changes in food intake or activity, suggesting that CaV1.1-mediated CaMKII activation impacts muscle energy expenditure. We delineate a pathway (Cav1.1→ CaMKII→ NOS) in normal skeletal muscle that regulates the intracellular distribution of the fatty acid transport protein, CD36, altering fatty acid metabolism. The consequences of blocking this pathway are decreased mitochondrial β-oxidation and decreased energy expenditure. This study delineates a previously uncharacterized CaV1.1-mediated pathway that regulates energy utilization in skeletal muscle.

Keywords: CD36; Ca2+ channel; Ca2+/calmodulin-dependent protein kinase II (CaMKII); CaM kinase II; CaV1.1; S-nitrosylation; calcium channel; metabolic rate; metabolism; mitochondria; mitochondrial beta oxidation; nitric-oxide synthase; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism*
  • Calcium / metabolism*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Energy Metabolism / physiology
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / metabolism*
  • Muscle, Skeletal / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Oxidation-Reduction


  • CACNA1S protein, mouse
  • CD36 Antigens
  • Calcium Channels, L-Type
  • Fatty Acids
  • Nitric Oxide Synthase
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium