TRPC5 ion channels are emerging drug targets, for example for CNS disorders, renal disease, cancer and cardiovascular disease (Cells 2018, 7, pii: E52). Furthermore TRPC5 is expressed in human perivascular fat, and acts as fatty acid sensor in adipocytes, where it regulates secretion of adiponectin, a major anti-inflammatory mediator (Circ. Res. 2012, 111:191). Inhibition of TRPC5 functionality can also reduce weight gain in mice on a high-cholesterol diet (Sci. Rep. 2019, 9, 773). However, fundamental and translational studies require a better understanding of TRPC5 channel regulation by endogenous and exogenous factors.
TRPC5 channels are hypothesised to be regulated by zinc (as Zn2+). Zn2+ has an insulin-like action on adipocytes, and its supplementation induces adipose tissue hypertrophy (Diabetes 1980, 29:665; Biol. Trace Elem. Res. 2017, 176:239). In addition, Zn2+-dependent activation of TRPC5 channels has been reported to contribute to cell death under oxidative stress conditions (Mol. Neurobiol. 2019, 56:2822), but the molecular mechanism of Zn2+ regulation of TRPC5 was not identified.
The aims of this project are to: 1) determine the molecular mechanism of TRPC5 regulation by Zn2+; and 2) evaluate the role of Zn2+ in TRPC5-mediated pathophysiological signalling in adipocytes.
The project will include the following types of experiments: 1) development of Zn2+-insensitive TRPC5 variants and their characterisation in functional ion channel assays (calcium imaging and/or patch clamp electrophysiology) and structural studies (cryo-EM); 2) measurement of effects of Zn2+ on intracellular calcium concentrations in adipocytes from wild-type and (available) Trpc5 knockout mice, and evaluation of functional changes such as glucose uptake, lipid storage/lysis and adipocytokine production.
The student will work in an established team of investigators with expertise in chemical biology, structural biology and physiology, and will benefit from available reagents, assays, structural data and tissues from wild-type and knockout mice.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
1. Minard A, Bauer CC, Wright DJ, Rubaiy HN, Muraki K, Beech DJ, Bon RS “Remarkable Progress with Small-Molecule Modulation of TRPC1/4/5 Channels: Implications for Understanding the Channels in Health and Disease.” Cells 2018, 7, pii: E52. doi:10.3390/cells7060052
2. Sukumar P, Sedo A, Li J, Wilson LA, O'Regan D, Lippiat JD, Porter KE, Kearney MT, Ainscough JF & Beech DJ. “Constitutively active TRPC channels of adipocytes confer a mechanism for sensing dietary fatty acids and regulating adiponectin.” Circulation Research 2012,111,191-200. doi:10.1161/circresaha.112.270751
3. Rawson S, Bisson C, Hurdiss DL, Fazal A, McPhillie MJ, Sedelnikova SE, Baker PJ, Rice DW, Muench SP. Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM. Procedures of the Natural Academy of Sciences of the United States of America 2018, 115, 1795-1800. doi:10.1073/pnas.1708839115