In a follow-up discovery published in the American Chemical Society journal, ACS Chemical Neuroscience , Professor Amitabha Chattopadhyay’s group from the CSIR-Centre for Cellular and Molecular Biology (CCMB) here has now shown that modulating the levels of cholesterol - an important lipid in the cell membrane - could change serotonin1A receptor's internal mechanism.
‘Serotonin1A receptor’ is one such important drug target in neuropsychiatric disorders such as anxiety and depression. Its function is regulated inside the cell through a process called endocytosis - a key event in the therapeutic action of several drugs, according to a release.
Cells in the human body body communicate with their surroundings through tiny nano-machines called G Protein-Coupled Receptors (GPCRs) present in its outermost membrane which are major drug targets in almost all clinical areas.
Statin addition helps therapy
Prof. Chattopadhyay’s team had previously shown that the serotonin1A receptor regulates through specialized regions of the cell membrane, called clathrin-coated pits, and later recycles into the cell membrane.
When CCMB researchers treated cells with statin - the best-selling cholesterol lowering drug in the market - they observed that the serotonin1A receptor, instead of using its regular clathrin-coated pits, used alternate regions called caveolae. “We observed that this switch in the mechanism of internal regulation reverted to clathrin-coated pits when we put back cholesterol in cells without statin treatment”, said G. Aditya Kumar, a Ph.D. student and first author of the paper.
Experiments from the team also revealed that receptors that usually recycle back to the cell membrane in normal conditions started getting degraded inside cells when they were treated with statin.
Anti-depressant drugs, termed selective serotonin reuptake inhibitors (SSRIs), target the endocytosis of serotonin1A receptor as their mechanism of action.
Novel insights
“These results show cholesterol modulates cells internal mechanism and could provide novel insights into improved therapeutic activity of antidepressant drugs when administered in combination with statins,” said Prof. Chattopadhyay.
These studies from CCMB are especially relevant in the Indian context since the National Mental Health Survey (2015-16) reported that more than five per cent of the adult Indian population suffers from depression.
