Progesterone interacts with the mutational hot-spot of TRPV4 and acts as a ligand relevant for fast Ca2+-signalling |
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| Affiliation: | 1. National Institute of Science Education and Research Bhubaneswar, School of Biological Sciences, P.O. Jatni, Khurda 752050, Odisha, India;2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India;1. School of Biotechnology, KIIT Deemed to be University, Patia, Bhubaneswar 751024, India;2. School of Chemical Technology, KIIT Deemed to be University, Patia, Bhubaneswar 751024, India;3. ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar 751002, India;4. Nanoelectronics and Device Physics Lab, School of Physical Science, National Institute of Science Education and Research, An OCC of HBNI, Jatni 752050, India;1. Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Departamento de Química, Cátedra de Química Biológica, Córdoba, Argentina;2. CONICET, Instituto de Investigaciones Biológicas y Tecnológicas (IIByT), Córdoba, Argentina;1. Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, United States of America;2. Department of Biology, University of Central Oklahoma, 100 North University Drive, Edmond, OK 73034, United States of America;1. Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, Netherlands;2. Zhejiang Provincial Key Laboratory of Food Microbiotechnology Research of China, the Zhejiang Gongshang University of China, Hangzhou, China;3. Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK;4. Antimicrobial Drug Discovery and Development, Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, L69 3BX Liverpool, UK |
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| Abstract: | Steroids are also known to induce immediate physiological and cellular response which occurs within minutes to seconds, or even faster. Such non-genomic actions of steroids are rapid and are proposed to be mediated by different ion channels. Transient receptor potential vanilloid sub-type 4 (TRPV4), is a non-specific polymodal ion channel which is involved in several physiological and cellular processes. In this work, we explored the possibilities of Progesterone (P4) as an endogenous ligand for TRPV4. We demonstrate that P4 docks as well as physically interacts with the TM4-loop-TM5 region of TRPV4, a region which is a mutational hotspot for different diseases. Live cell imaging experiments with a genetically encoded Ca2+-sensor suggests that P4 causes quick influx of Ca2+ specifically in the TRPV4 expressing cells, which can be partially blocked by TRPV4-specific inhibitor, suggesting that P4 can act as a ligand for TRPV4. Such P4-mediated Ca2+-influx is altered in cells expressing disease causing TRPV4 mutants, namely in L596P, R616Q, and also in embryonic lethal mutant L618P. P4 dampens, both in terms of “extent” as well as the “pattern” of the Ca2+-influx by other stimulus too in cells expressing TRPV4-Wt, suggesting that P4 crosstalk with the TRPV4-mediated Ca2+-signalling, both in quick and long-term manner. We propose that P4 crosstalk with TRPV4 might be relevant for both acute and chronic pain as well as for other health-related functions. |
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