A molecular sensor for cholesterol
doi:10.1038/nindia.2021.115 Published online 30 August 2021
Neurotransmitter receptors are membrane-bound proteins that aid cell-to-cell communications in the nervous system. Researchers from the CSIR-Centre for Cellular and Molecular Biology (CCMB) in Hyderabad have now discovered that one such neurotransmitter receptor could sense the changes in the levels of membrane cholesterol1.
The researchers identified a specific amino acid in the receptor that enables it to bind and sense the changes in the levels of cholesterol.
The researchers say that these findings are important since cholesterol levels in cells change with age and in diseases. This work, they say, will be useful for developing better drugs because the receptor is a known drug target.
Previous studies had shown that the membrane cholesterol modulates the function of the receptor that belongs to the family of serotonin receptors. However, it remains unknown how the membrane cholesterol modulates the receptor’s activity.
To shed light on this, the CCMB scientists expressed the serotonin1A receptor in specific cultured human cells. The researchers, led by Amitabha Chattopadhyay, found that the receptor reduced the levels of cyclic adenosine monophosphate (cAMP) by inhibiting the activity of a specific enzyme.
Depleting the membrane cholesterol in the cultured cells disrupted the receptor’s function. It could not reduce cAMP levels, proving that the membrane cholesterol could modify the receptor’s function.
Next, the researchers induced a mutation in the gene that encodes the receptor. This mutation changed an amino acid at a cholesterol-binding site of the receptor. Such a mutation robbed the receptor of its ability to bind to the membrane cholesterol.
1. Kumar, G. A. et al. A molecular sensor for cholesterol in the human serotonin1A receptor. Sci. Adv.7, eabh2922 (2021) Doi:10.1126/sciadv.abh2922