期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 31, 页码 15540-15549出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902917116
关键词
ion channels; biophysics; TRP channels; gating mechanisms; polycystins
资金
- Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology (ASN)
- Mayo Clinic Robert M. and Billie Kelley Pirnie Translational PKD Research Center (National Institute of Diabetes and Digestive and Kidney Disease [NIDDK]) [P30 DK090728]
- Polycystic Kidney Disease Foundation
- Northwestern University Center for Kidney Research and Therapeutics research grant (NU Go KIDNEY)
- NIDDK [R00DK106655, R56DK119709]
- ASN Foundation for Kidney Research
The opening of voltage-gated ion channels is initiated by transfer of gating charges that sense the electric field across the membrane. Although transient receptor potential ion channels (TRP) are members of this family, their opening is not intrinsically linked to membrane potential, and they are generally not considered voltage gated. Here we demonstrate that TRPP2, a member of the polycystin subfamily of TRP channels encoded by the PKD2L1 gene, is an exception to this rule. TRPP2 borrows a biophysical riff from canonical voltage-gated ion channels, using 2 gating charges found in its fourth transmembrane segment (S4) to control its conductive state. Rosetta structural prediction demonstrates that the S4 undergoes similar to 3- to 5-angstrom transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation-p interactions within the voltage sensor domain (VSD) during membrane depolarization. Our data demonstrate that the transfer of a single gating charge per channel subunit is requisite for voltage, temperature, and osmotic swell polymodal gating of TRPP2. Taken together, we find that irrespective of stimuli, TRPP2 channel opening is dependent on activation of its VSDs.
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