Mechanosensitive Piezo Channels in the Gastrointestinal Tract

Abstract

Sensation of mechanical forces is critical for normal function of the gastrointestinal (GI) tract and abnormalities in mechanosensation are linked to GI pathologies. In the GI tract there are several mechanosensitive cell types-epithelial enterochromaffin cells, intrinsic and extrinsic enteric neurons, smooth muscle cells and interstitial cells of Cajal. These cells use mechanosensitive ion channels that respond to mechanical forces by altering transmembrane ionic currents in a process called mechanoelectrical coupling. Several mechanosensitive ionic conductances have been identified in the mechanosensory GI cells, ranging from mechanosensitive voltage-gated sodium and calcium channels to the mechanogated ion channels, such as the two-pore domain potassium channels K2P (TREK-1) and nonselective cation channels from the transient receptor potential family. The recently discovered Piezo channels are increasingly recognized as significant contributors to cellular mechanosensitivity. Piezo1 and Piezo2 are nonselective cationic ion channels that are directly activated by mechanical forces and have well-defined biophysical and pharmacologic properties. The role of Piezo channels in the GI epithelium is currently under investigation and their role in the smooth muscle syncytium and enteric neurons is still not known. In this review, we outline the current state of knowledge on mechanosensitive ion channels in the GI tract, with a focus on the known and potential functions of the Piezo channels.

Keywords: Enteric nervous system; Enterochromaffin cell; Gastrointestinal; Interstitial cell of Cajal; Mechanosensation; Mechanosensitive; Mechanosensitive ion channel; Mechanotransduction; Neuron; Piezo; Smooth muscle cell; Voltage-gated channels.

Figure 1

Mechanosensitive cells in the gastrointestinal (GI) tract. Mechanosensitive cells in the GI tract include epithelial enterochromaffin cells, smooth muscle cells (SMCs), interstitial cells of Cajal (ICCs), intrinsic neurons, including interneurons, intesti-nofugal neurons, and extrinsic neurons.

Figure 2

Piezo2 is important for enterochromaffin (EC) cell mechanotransduction. Immunohistochemistry showing that mouse (A) TPH1-CFP positive EC cells [red] label with (B) Piezo2 [green] (C). Nuclei labeled with DAPI, scale bar 10 µm. (D) Inward currents evoked by mechanical stimulation of EC cell model (QGP-1) are rapidly activating and inactivating [red line]. Blue trace represents peak current. (E) Current-deformation data are fit with two-state Boltzmann [red line] and (F) current―voltage relationship is linear [red line]. (G) The mechanically induced inward currents are blocked by Gd³⁺, D-GsMTx-4, and Piezo2 siRNA. (H) Averaged peak current in control QGP-1 cells is inhibited by Gd³⁺, D-GsMTx-4, and Piezo2 siRNA but not nontargeting (NT) siRNA. *p < .05 compared to no stretch. #p < .05 compared to NT siRNA. (I) Blockade of stretch-dependent 5-HT release from EC cell model QGP-1 by Piezo channel blockers Gd³⁺, D-GsMTx-4, RR, and Piezo2 siRNA but not NT siRNA. *p < .05. #p > .05 compared to stretch. Modified with permission from Wang, F., Knutson, K., Alcaino, C., Linden, D. R., Gibbons, S. J., Kashyap, P. K., . Beyder, A. (2016). Mechano-sensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces. The Journal of Physiology. http://dx.doi.org/10.1113/JP272718.