Differential effects of cholesterol and desmosterol on the ligand binding function of the hippocampal serotonin1A receptor: Implications in desmosterolosis

Abstract

Cholesterol is a unique molecule in terms of high level of in-built stringency, fine tuned by natural evolution for its ability to optimize physical properties of higher eukaryotic cell membranes in relation to biological functions. We previously demonstrated the requirement of membrane cholesterol in maintaining the ligand binding activity of the hippocampal serotonin(1A) receptor. In order to test the molecular stringency of the requirement of cholesterol, we depleted cholesterol from native hippocampal membranes followed by replenishment with desmosterol. Desmosterol is an immediate biosynthetic precursor of cholesterol in the Bloch pathway differing only in a double bond at the 24th position in the alkyl side chain. Our results show that replenishment with desmosterol does not restore ligand binding activity of the serotonin(1A) receptor although replenishment with cholesterol led to significant recovery of ligand binding. This is in spite of similar membrane organization (order) in these membranes, as monitored by fluorescence anisotropy measurements. The requirement for restoration of ligand binding activity therefore appears to be more stringent than the requirement for the recovery of overall membrane order. These novel results have potential implications in understanding the interaction of membrane lipids with this important neuronal receptor in diseases such as desmosterolosis.

Molecular rheology of neuronal membranes explored using a molecular rotor: Implications for receptor function

“…An important aspect of our results is that the interaction between cholesterol and the serotonin1A receptor appears to be stringent, since immediate biosynthetic precursors of cholesterol (differing with cholesterol merely in a double bond) were not able to maintain receptor function (Paila et al, 2008;Singh et al, 2009). In addition, we recently showed that the requirement of cholesterol for receptor function is diastereospecific, but not enantiospecific (Jafurulla et al, 2014).…”

A comparative study of the effects of cholesterol and desmosterol on zwitterionic DPPC model membranes

“…In the literature, defects in the cholesterol biosynthetic pathway have been identified with some 42 hereditary metabolic diseases (Shrivastava et al, 2008;Chatto-43 padhyay et al, 2007;Herman, 2003;Kelley and Herman, 2001;44 Megha et al, 2006;Waterham, 2006;Waterham et al, 2001). The 45 inability to transform desmosterol into cholesterol results in a 46 human disease, desmosterolosis (Róg et al, 2008) (Singh et al, 2009). For this reason, 56 desmosterol is of medical interest and the studies investigating the 57 differential effects of cholesterol and its precursors on membranes 58 are very important.…”

Comparison of the liquid-ordered bilayer phases containing cholesterol or 7-dehydrocholesterol in modeling Smith-Lemli-Opitz syndrome

“…Desmosterol, a closely related structure with an extra double bond ( ⌬ 24) on the hydrocarbon side chain and also an immediate precursor of cholesterol in the Steinberg biosynthesis pathway, was also unable to substitute for cholesterol in the restoration of serotonin binding ( 38 ). Taken together, such biological studies have rarely received supporting evidence from detailed biophysical measurements to give credence to the concept proposed earlier by Bloch ( 39 ) that the "structural details of the cholesterol molecule and related sterols can be rationalized in terms of optimal hydrophobic interactions between the planar sterol ring system (and lateral side chain) and phospholipid acyl chains or ceramides" ( 21 ).…”