Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin 1A Receptor
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Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor Parijat Sarkar1 · Md. Jafurulla1 · Sukanya Bhowmick1,2 · Amitabha Chattopadhyay1 Received: 16 July 2020 / Accepted: 4 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The role of membrane cholesterol in modulating G protein-coupled receptor (GPCR) structure and function has emerged as a powerful theme in contemporary biology. In this paper, we report the subtlety and stringency involved in the interaction of sterols with the s erotonin1A receptor. For this, we utilized two immediate biosynthetic precursors of cholesterol, 7-dehydrocholesterol (7-DHC) and desmosterol, which differ with cholesterol merely in a double bond in their chemical structures in a position-dependent manner. We show that whereas 7-DHC could not support the ligand binding function of the s erotonin1A receptor in live cells, desmosterol could partially support it. Importantly, depletion and enrichment of membrane cholesterol over basal level resulted in an increase and reduction of the basal receptor activity, respectively. These results demonstrate the relevance of optimal membrane cholesterol in maintaining the activity of the serotonin1A receptor, thereby elucidating the relevance of cellular cholesterol homeostasis. Graphic Abstract
Enhanced receptor activity Cholesterol depletion
Reduced receptor activity Cholesterol enrichment
Optimum membrane cholesterol
7-DHC replenishment
Normal serotonin1A receptor activity
Enhanced receptor activity
Desmosterol replenishment
Partially enhanced receptor activity
Keywords Serotonin1A receptor · 7-Dehydrocholesterol/desmosterol · Optimum membrane cholesterol Extended author information available on the last page of the article
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Introduction G protein-coupled receptors (GPCRs) are the largest class of receptors in the plasma membrane that transduce extracellular signals to the cellular interior. They are characterized by a seven transmembrane domain architecture connected by three extracellular and three intracellular loops (Pierce et al. 2002; Rosenbaum et al. 2009; Venkatakrishnan et al. 2013; Chattopadhyay 2014; Pal and Chattopadhyay 2019). GPCRs are crucial communication hubs on the cell membrane and facilitate a wide array of cellular signaling processes upon binding to a diverse variety of ligands (Ghosh et al. 2014; Wacker et al. 2017). As a consequence of the varied range of physiological processes regulated by GPCRs, these receptors are the most popular therapeutic targets and ~ 40% of approved drugs in the current market act on GPCRs (Insel et al. 2019). Due to the intimate association of GPCRs with the plasma membrane due to their heptahelical architecture, the interaction of GPCRs with lipids in their immediate microenvironment assumes relevance. In this context, the interplay between GPCRs and membrane cholesterol has emerged as a major area of research in GPCR biology. Extensive work using biochemi
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