Piezo proteins: regulators of mechanosensation and other cellular processes

Abstract

Piezo proteins have recently been identified as ion channels mediating mechanosensory transduction in mammalian cells. Characterization of these channels has yielded important insights into mechanisms of somatosensation, as well as other mechano-associated biologic processes such as sensing of shear stress, particularly in the vasculature, and regulation of urine flow and bladder distention. Other roles for Piezo proteins have emerged, some unexpected, including participation in cellular development, volume regulation, cellular migration, proliferation, and elongation. Mutations in human Piezo proteins have been associated with a variety of disorders including hereditary xerocytosis and several syndromes with muscular contracture as a prominent feature.

Keywords: Arthrogryposis; Genetic Disease; Gordon Syndrome; Hereditary Xerocytosis; Ion Channel; Mechanotransduction; Membrane Protein; Neuron; Piezo1; Piezo2; Somatosensation.

FIGURE 1.

Models of human PIEZO1 and PIEZO2. A and B, predicted membrane topology models of PIEZO1 (panel A, UniProt accession number Q92508) and PIEZO2 (panel B, UniProt accession number Q9H5I5) were created using Swiss-Prot prediction tools and the methodology of Eisenberg et al. (74). The locations of PIEZO1 mutations identified in hereditary xerocytosis (A) and PIEZO2 mutations identified in DA5, GS, and MWS (B) are marked. aa, amino acids.

FIGURE 2.

Evolutionary relationships of Piezo proteins. A phylogenetic tree based on comparison of Piezo protein sequences illustrating the relationships of Piezo proteins between species is shown. A single Piezo protein is present in lower species, including plants, worms, and flies. Near the base of the vertebrate tree, Piezo proteins were duplicated. The presence of more than one protein infers that the Piezo proteins have acquired additional functions. C. elegans, Caenorhabditis elegans.

FIGURE 3.

A highly conserved region in Piezo proteins. Multiple sequence alignment of Piezo proteins reveals a highly conserved region across species in the COOH terminus of Piezo proteins from plants to humans. This absolutely conserved region, the PFEW motif, is shown with amino acids comprising this motif shaded.

FIGURE 4.

Mechano-activated Piezo currents. A, representative whole-cell currents in HEK293 cells expressing murine Piezo2. Mechanical stimulation was delivered by a glass probe affixed to a piezoelectricity-driven actuator at 800 μm/s velocity in steps of 1.0 μm (4). B, wild type and mutant R2456H PIEZO1. Representative peak-normalized traces of mechanically activated, whole-cell currents recorded from HEK293 cells expressing wild type (black trace) or mutant R2456H (blue trace) PIEZO1 at −80 mV are shown. The stimulus waveform at 11 μm is shown above the current traces. The PIEZO1 R2456H mutation exhibits slower inactivation kinetics.