CCMB's study throws new insights on improving therapeutic activity of Antidepressants

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Serotonin1A receptor's internal activity could be altered by regulation of cholesterol, which is an important lipid in the cell membrane. This follow-up discovery has been made by Professor Amitabha Chattopadhyay’s group from the CSIR-Centre for Cellular and Molecular Biology (CCMB) and was published in the American Chemical Society journal, ACS Chemical Neuroscience.

A release showed that endocytosis is a key event in the therapeutic action of several drugs. It is responsible for controlling the function of serotonin1A receptor, which is one of the important drug targets in neuropsychiatric disorders such as anxiety and depression. A drug target is mostly a protein, which could be actioned upon by a drug to produce desired therapeutic effect in a disease.

G Protein-Coupled Receptors (GPCRs) are molecules that enable communication between cells and are located in the outermost cell membrane. These are major drug targets in almost all clinical conditions.

 Selective serotonin reuptake inhibitors (SSRIs), which are common antidepressants, target the endocytosis of serotonin1A receptor in their procedure of action.

FINDINGS OF THE STUDY

Serotonin1A receptor regulates through specialized regions of the cell membrane called clathrin-coated pits. It later gets transferred or recycled into the cell membrane. 

It was observed that Serotonin1A receptor used alternate regions called caveolae instead of these clathrin-coated pits, when cells were treated with statin, a common cholesterol lowering drug. Also, statin treatment led to the backward movement of receptors into the cell, which otherwise would go into cell membrane in normal conditions.

“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.

Improved therapeutic activity of antidepressants

Prof. Chattopadhyay stated, "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".

National Mental Health Survey (2015-16) has revealed that above than five per cent of the adult Indian population suffers from depression. In such scenario, it is hoped that studies like these by CCMB will prove as a boon in addressing mental healthcare of Indians and people worldwide.



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