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Activation of TRPP2 through mDia1-dependent voltage gating
Chang-Xi Bai1, Sehyun Kim, Wei-Ping Li
1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
The EMBO Journal
|April 5, 2008
Summary
Mammalian diaphanous-related formin 1 (mDia1) regulates the TRPP2 channel by voltage-dependent blocking. Epidermal growth factor (EGF) activates TRPP2 by releasing this mDia1 block via RhoA signaling.
Area of Science:
- Ion channel regulation
- Molecular mechanisms of kidney disease
- TRP channel gating
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is linked to TRPP2 cation channel dysfunction.
- The fundamental mechanisms of TRPP2 channel gating and activation remain largely unknown.
- Previous studies indicated TRPP2 activation by EGF and interaction with mDia1, a RhoA effector.
Purpose of the Study:
- To elucidate the role of mDia1 in TRPP2 channel regulation.
- To investigate the voltage-dependent gating mechanisms of TRPP2.
- To understand how EGF and RhoA signaling influence TRPP2 activity.
Main Methods:
- Electrophysiological recordings to assess TRPP2 channel activity.
- Co-immunoprecipitation to confirm physical interaction between TRPP2 and mDia1.
- RhoA activation assays and mDia1 autoinhibition/activation state analysis.
Main Results:
- mDia1 specifically blocks TRPP2 channel activity at negative membrane potentials.
- This block is relieved at positive potentials, allowing TRPP2 channel function.
- RhoA activation induces a conformational switch in mDia1, transitioning it from an autoinhibited to an active state.
- EGF stimulation activates TRPP2 by promoting RhoA-mediated release of the mDia1 block.
Conclusions:
- mDia1 plays a novel role in regulating ion channel function through voltage-dependent mechanisms.
- RhoA signaling and mDia1 mediate voltage-dependent gating of TRPP2 channels.
- This study provides a molecular basis for TRPP2 channel regulation in the context of ADPKD and TRP channel physiology.
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