Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Md Jafurulla, Bhagyashree D. Rao, Sugunan Sreedevi, Jean Marie Ruysschaert, Douglas F. Covey, Amitabha Chattopadhyay

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol), for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction.

Original languageEnglish
Pages (from-to)158-163
Number of pages6
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1838
Issue number1 PARTB
DOIs
StatePublished - 2014

Keywords

  • Cholesterol
  • Fluorescence anisotropy
  • Ligand binding
  • Serotonin receptor
  • ent-Cholesterol
  • epi-Cholesterol

Fingerprint

Dive into the research topics of 'Stereospecific requirement of cholesterol in the function of the serotonin1A receptor'. Together they form a unique fingerprint.

Cite this