The serotonin1A receptor is an important member of the
G-protein coupled receptor family, and is involved in the generation and modulation of a variety of cognitive, behavioral, and developmental functions. Solubilization of the hippocampal serotonin1A receptor by 3-[(3-cholamidopropyl)-dimethylammonio]-1-
propanesulfonate (
CHAPS) is accompanied by loss of membrane
cholesterol which results in a reduction in specific agonist binding activity. Replenishment of
cholesterol to solubilized membranes restores the
cholesterol content of the membrane and significantly enhances specific agonist binding activity. In order to test the stringency of the requirement of
cholesterol in this process, we solubilized native hippocampal membranes followed by replenishment with
7-dehydrocholesterol (7-DHC).
7-DHC is an immediate biosynthetic precursor of
cholesterol differing only in a double bond at the 7th position in its
sterol ring. Our results show, for the first time, that replenishment of solubilized hippocampal membranes with
7-DHC does not restore
ligand binding activity of the serotonin1A receptor, in spite of recovery of the overall membrane order. This observation shows that the requirement for restoration of
ligand binding activity is more stringent than the requirement for the recovery of overall membrane order. These novel results have potential implications in understanding the interaction of membrane
sterols with this important neuronal receptor under pathogenic conditions such as the
Smith-Lemli-Opitz syndrome.