TY - JOUR

T1 - Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor

AU - Sarkar, Parijat

AU - Jafurulla, Md

AU - Bhowmick, Sukanya

AU - Chattopadhyay, Amitabha

N1 - Funding information: This work was supported by SERB Distinguished Fellowship grant (Department of Science and Technology, Govt. of India) to A.C. and core support from CSIR-Centre for Cellular and Molecular Biology. P.S. thanks the Council of Scientific and Industrial Research for the award of a Shyama Prasad Mukherjee Fellowship. We thank members of the Chattopadhyay laboratory for critically reading the manuscript and for their comments. This work was supported by SERB Distinguished Fellowship grant (Department of Science and Technology, Govt. of India) to A.C. and core support from CSIR-Centre for Cellular and Molecular Biology. P.S. thanks the Council of Scientific and Industrial Research for the award of a Shyama Prasad Mukherjee Fellowship. We thank members of the Chattopadhyay laboratory for critically reading the manuscript and for their comments.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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 serotonin 1A 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 serotonin 1A 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 serotonin 1A receptor, thereby elucidating the relevance of cellular cholesterol homeostasis.

AB - 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 serotonin 1A 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 serotonin 1A 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 serotonin 1A receptor, thereby elucidating the relevance of cellular cholesterol homeostasis.

KW - 7-Dehydrocholesterol/desmosterol

KW - Optimum membrane cholesterol

KW - Serotonin receptor

UR - http://www.scopus.com/inward/record.url?scp=85091058088&partnerID=8YFLogxK

U2 - 10.1007/s00232-020-00138-x

DO - 10.1007/s00232-020-00138-x

M3 - Article

C2 - 32949248

AN - SCOPUS:85091058088

VL - 253

SP - 445

EP - 457

JO - Journal of Membrane Biology

JF - Journal of Membrane Biology

SN - 0022-2631

IS - 5

ER -