The Molecular Mechanism of Mechanosensitivity in K2P Channels
نوع المنشور
ورقة مؤتمر
النص الكامل

The two-pore domain (K2P) potassium channels of the TREK family are modulated by various chemical and physical stimuli, including extra- and intracellular protons, temperature and mechanical force. Here, using the prototypical mechanosensitive K2Pchannel K2P2.1 (KCNK2/TREK-1) as a model, we investigated the molecular mechanism through which mechanical force affects K2P channel function.

In agreement with earlier data (Bagriantsev S, Minor D et al, 2011; Piechotta P, Baukrowitz T et al., 2011), we found that progressive stabilization of the selectivity filter in an open conformation by mutations suppresses mechanosensitivity, suggesting that application of mechanical force leads to channel opening at the extracellular gate. However, mutations that prevent cross-communication between the gate and the intracellular C-terminal domain (Bagriantsev S, Minor D et al., 2012) abrogate mechanical responses, without affecting other functions of the gate. These results demonstrate that the pore-forming domain of K2P2.1 lacks intrinsic mechanosensitivity and requires allosteric coupling with the C-terminal domain in order to respond to mechanical stimulation.

The absence of intrinsic mechanosensitivity in the pore-forming domain of K2P2.1 contrasts the mechanism proposed for mechanosensitive prokaryotic ion channels (Sukharev S, Sachs S, 2012) and the yeast channel TRPY1 (Su Z, Saimi Y et al., 2011), where deformation of the plasma membrane by mechanical force is thought to directly affect channel activity by stretching the pore. Our data suggest that in K2P2.1, a modular intracellular domain serves as a mechano-sensor that triggers opening of a mechano-insensitive selectivity filter-based gate. These findings highlight the existence of modular sensory and gating domains in K2P channel structure, and suggest a novel mechanism of mechanosensitivity in eukaryotic ion channels.

عنوان المؤتمر
Biophysical society | 58th Annual Meeting
دولة المؤتمر
الولايات المتحدة الأمريكية
تاريخ المؤتمر
15 فبراير، 2014 - 19 فبراير، 2014
راعي المؤتمر
Yale University
معلومات إضافية
موقع المؤتمر الإلكتروني