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  • The EMBO Journal (2008) 27, 1345 - 1356
  • doi:10.1038/emboj.2008.70

Published online: 3 April 2008

Activation of TRPP2 through mDia1-dependent voltage gating

Chang-Xi Bai1, Sehyun Kim1, Wei-Ping Li1,a, Andrew J Streets2, Albert C M Ong2 and Leonidas Tsiokas1

  1. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  2. Kidney Genetics Group, Academic Nephrology Unit, The Henry Wellcome Laboratories for Medical Research, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

Correspondence to:

Leonidas Tsiokas, Department of Cell Biology, University of Oklahoma Health Sciences Center, 975 NE 10th str, BRC1/262, Oklahoma City, OK 73104, USA. Tel.: +01 405 271 8001 ext 46211; Fax: +01 405 271 3758; E-mail: leonidas-tsiokas@ouhsc.edu

aPresent address: Department of Pharmacology, Anhui Medical University, Hefei, Anhui Province 230032, People's Republic of China

Received 31 October 2007; Accepted 14 March 2008

The TRPP2 cation channel is directly responsible for approx15% of all cases of autosomal dominant polycystic kidney disease. However, the mechanisms underlying fundamental properties of TRPP2 regulation, such as channel gating and activation, are unknown. We have shown that TRPP2 was activated by EGF and physically interacted with the mammalian diaphanous-related formin 1 (mDia1), a downstream effector of RhoA. Now, we show that mDia1 regulates TRPP2 by specifically blocking its activity at negative but not positive potentials. The voltage-dependent unblock of TRPP2 by mDia1 at positive potentials is mediated through RhoA-induced molecular switching of mDia1 from its autoinhibited state at negative potentials to its activated state at positive potentials. Under physiological resting potentials, EGF activates TRPP2 by releasing the mDia1-dependent block through the activation of RhoA. Our data reveal a new role of mDia1 in the regulation of ion channels and suggest a molecular basis for the voltage-dependent gating of TRP channels.

  • Keywords:

    • autosomal dominant polycystic kidney disease,
    • mDia1,
    • RhoA,
    • TRP channels,
    • TRPP2