Molecular Neurobiology

, Volume 50, Issue 1, pp 149–158

Sterol Carrier Protein-2: Binding Protein for Endocannabinoids

  • Elizabeth Sabens Liedhegner
  • Caleb D. Vogt
  • Daniel S. Sem
  • Christopher W. Cunningham
  • Cecilia J. Hillard


The endocannabinoid (eCB) system, consisting of eCB ligands and the type 1 cannabinoid receptor (CB1R), subserves retrograde, activity-dependent synaptic plasticity in the brain. eCB signaling occurs “on-demand,” thus the processes regulating synthesis, mobilization and degradation of eCBs are also primary mechanisms for the regulation of CB1R activity. The eCBs, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are poorly soluble in water. We hypothesize that their aqueous solubility, and, therefore, their intracellular and transcellular distribution, are facilitated by protein binding. Using in silico docking studies, we have identified the nonspecific lipid binding protein, sterol carrier protein 2 (SCP-2), as a potential AEA binding protein. The docking studies predict that AEA and AM404 associate with SCP-2 at a putative cholesterol binding pocket with ∆G values of −3.6 and −4.6 kcal/mol, respectively. These values are considerably higher than cholesterol (−6.62 kcal/mol) but consistent with a favorable binding interaction. In support of the docking studies, SCP-2-mediated transfer of cholesterol in vitro is inhibited by micromolar concentrations of AEA; and heterologous expression of SCP-2 in HEK 293 cells increases time-related accumulation of AEA in a temperature-dependent fashion. These results suggest that SCP-2 facilitates cellular uptake of AEA. However, there is no effect of SCP-2 transfection on the cellular accumulation of AEA determined at equilibrium or the IC50 values for AEA, AM404 or 2-AG to inhibit steady state accumulation of radiolabelled AEA. We conclude that SCP-2 is a low affinity binding protein for AEA that can facilitate its cellular uptake but does not contribute significantly to intracellular sequestration of AEA.


N-Arachidonylethanolamine 2-Arachidonoylglycerol AM404 Cholesterol Uptake Sequestration AutoDock 







Analysis of variance


Type 1 cannabinoid receptor




Endocannabinoid signaling


Sterol carrier protein 2

Supplementary material

12035_2014_8651_MOESM1_ESM.docx (1.7 mb)
ESM 1(DOCX 1740 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Elizabeth Sabens Liedhegner
    • 1
  • Caleb D. Vogt
    • 2
  • Daniel S. Sem
    • 2
  • Christopher W. Cunningham
    • 2
  • Cecilia J. Hillard
    • 1
  1. 1.Neuroscience Research Center and Departments of Pharmacology and ToxicologyMedical College of WisconsinMilwaukeeUSA
  2. 2.Department of Pharmaceutical SciencesConcordia University of Wisconsin, School of PharmacyMequonUSA

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