Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors

Biochemistry. 2010 Jul 6;49(26):5426-35. doi: 10.1021/bi100276b.


Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme in cholesterol biosynthesis, and are some of the best selling drugs globally. We have explored the effect of chronic cholesterol depletion induced by mevastatin on the function of human serotonin(1A) receptors expressed in CHO cells. An advantage with statins is that cholesterol depletion is chronic which mimics physiological conditions. Our results show a significant reduction in the level of specific ligand binding and G-protein coupling to serotonin(1A) receptors upon chronic cholesterol depletion, although the membrane receptor level is not reduced at all. Interestingly, replenishment of mevastatin-treated cells with cholesterol resulted in the recovery of specific ligand binding and G-protein coupling. Treatment of cells expressing serotonin(1A) receptors with mevastatin led to a decrease in the diffusion coefficient and an increase in the mobile fraction of the receptor, as determined by fluorescence recovery after photobleaching measurements. To the best of our knowledge, these results constitute the first report describing the effect of chronic cholesterol depletion on the organization and function of a G-protein-coupled neuronal receptor. Our results assume significance in view of recent reports highlighting the symptoms of anxiety and depression in humans upon statin administration, and the role of serotonin(1A) receptors in anxiety and depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / etiology
  • CHO Cells
  • Cholesterol / deficiency*
  • Chronic Disease
  • Cricetinae
  • Cricetulus
  • Depression / etiology
  • GTP-Binding Proteins / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Ligands
  • Lovastatin / analogs & derivatives
  • Lovastatin / pharmacology
  • Protein Binding / drug effects
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, G-Protein-Coupled / metabolism


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptor, Serotonin, 5-HT1A
  • mevastatin
  • Cholesterol
  • Lovastatin
  • GTP-Binding Proteins