Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Department of Physiology and Membrane Biology, University of California, Davis, CA 95616.
Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15540-15549. doi: 10.1073/pnas.1902917116. Epub 2019 Jul 17.
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 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 ∼3- to 5-Å transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation-π 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.
电压门控离子通道的开启是由门控电荷的转移引发的，这些门控电荷感知跨膜的电场。尽管瞬时受体电位离子通道（TRP）是该家族的成员，但它们的开启与膜电位没有内在联系，通常不被认为是电压门控的。在这里，我们证明了 TRPP2，一种由基因编码的多房性蛋白亚家族的 TRP 通道成员，是该规则的一个例外。TRPP2 从经典的电压门控离子通道借用了一种物理特性，利用其第四跨膜片段（S4）中的 2 个门控电荷来控制其传导状态。罗塞塔结构预测表明，S4 在去极化过程中发生约 3-5Å 的过渡和侧向运动，这与通道孔的开启相偶联。在这里，在膜去极化过程中，两个门控电荷在电压传感器结构域（VSD）内形成状态依赖性的阳离子-π相互作用。我们的数据表明，每个通道亚基的单个门控电荷的转移对于 TRPP2 的电压、温度和渗透肿胀多模态门控是必需的。总之，我们发现无论刺激如何，TRPP2 通道的开启都依赖于其 VSD 的激活。
