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Exploring Endocytosis and Intracellular Trafficking of the Human Serotonin₁A Receptor

Author:
Kumar, G. Aditya, Sarkar, Parijat, Jafurulla, Md., Singh, Shishu Pal, Srinivas, Gunda, Pande, Gopal, Chattopadhyay, Amitabha
Source:
Biochemistry 2019 v.58 no.22 pp. 2628-2641
ISSN:
1520-4995
Subject:
G-protein coupled receptors, antidepressants, anxiety, endocytosis, endosomes, flow cytometry, human cell lines, humans, image analysis, physiological transport, plasma membrane, signal transduction
Abstract:
G protein-coupled receptors (GPCRs) represent the largest class of receptors involved in signal transduction across cell membranes and are major drug targets in all clinical areas. Endocytosis of GPCRs offers a regulatory mechanism for sustaining their signaling within a stringent spatiotemporal regime. In this work, we explored agonist-induced endocytosis of the human serotonin₁A receptor stably expressed in HEK-293 cells and the cellular machinery involved in receptor internalization and intracellular trafficking. The serotonin₁A receptor is a popular GPCR implicated in neuropsychiatric disorders such as anxiety and depression and serves as an important drug target. In spite of its pharmacological relevance, its mechanism of endocytosis and intracellular trafficking is less understood. In this context, we have utilized a combination of robust population-based flow cytometric analysis and confocal microscopic imaging to address the path and fate of the serotonin₁A receptor during endocytosis. Our results, utilizing inhibitors of specific endocytosis pathways and intracellular markers, show that the serotonin₁A receptor undergoes endocytosis predominantly via the clathrin-mediated pathway and subsequently recycles to the plasma membrane via recycling endosomes. These results would enhance our understanding of molecular mechanisms of GPCR endocytosis and could offer novel insight into the underlying mechanism of antidepressants that act via the serotonergic pathway. In addition, our results could be relevant in understanding cell (or tissue)-specific GPCR endocytosis.
Agid:
6459618