Touch, Tension, and Transduction – The Function and Regulation of Piezo Ion Channels

Piezo proteins were identified in 2010 as the pore-forming subunits of excitatory mechanosensitive ion channels. Piezo ion channels play essential roles in diverse physiological processes ranging from regulation of red blood cell volume to sensation of gentle touch, and are associated with a number of diseases. A recent medium-resolution structure gives insight into the overall architecture of Piezo1, but does not give straight answers as to how the channel transduces mechanical force into pore opening. The function of Piezos, including the inactivation mechanism, can be modulated by many factors both intrinsic and extrinsic to the channel. In 2010, two proteins, Piezo1 and Piezo2, were identified as the long-sought molecular carriers of an excitatory mechanically activated current found in many cells. This discovery has opened the floodgates for studying a vast number of mechanotransduction processes. Over the past 6 years, groundbreaking research has identified Piezos as ion channels that sense light touch, proprioception, and vascular blood flow, ruled out roles for Piezos in several other mechanotransduction processes, and revealed the basic structural and functional properties of the channel. Here, we review these findings and discuss the many aspects of Piezo function that remain mysterious, including how Piezos convert a variety of mechanical stimuli into channel activation and subsequent inactivation, and what molecules and mechanisms modulate Piezo function. In 2010, two proteins, Piezo1 and Piezo2, were identified as the long-sought molecular carriers of an excitatory mechanically activated current found in many cells. This discovery has opened the floodgates for studying a vast number of mechanotransduction processes. Over the past 6 years, groundbreaking research has identified Piezos as ion channels that sense light touch, proprioception, and vascular blood flow, ruled out roles for Piezos in several other mechanotransduction processes, and revealed the basic structural and functional properties of the channel. Here, we review these findings and discuss the many aspects of Piezo function that remain mysterious, including how Piezos convert a variety of mechanical stimuli into channel activation and subsequent inactivation, and what molecules and mechanisms modulate Piezo function. a family of disorders including distal arthrogryposis type 5, Gordon syndrome, and Marden–Walker syndrome. Patients with these disorders all exhibit congenital joint contractures (or abnormal stiffness of joints), but can be distinguished by other, specific symptoms. a process in which a channel initially opens in response to a stimulus but over time, despite the continued presence of the stimulus, ceases to conduct ions (closes). a disease caused by dysfunction of an ion channel, often resulting from a mutation in the channel gene. a disease characterized by severe swelling, or lymphedema, in the limbs. a disease characterized by dehydration of red blood cells, resulting in increased fragility of these cells and subsequent anemia. The dehydrated cells have a cup shape, and are often referred to as stomatocytes. sensory neurons with afferents that terminate in the spinal cord, and with sensitivity to mechanical touch, temperature, and specific chemicals. an experimental device allowing precise (±1 mmHg) and rapid (∼10 ms) control of pressure (both negative and positive). It is used to mechanically stimulate a channel-containing membrane patch within a pipette during an electrophysiological recording (Figure 1). a difference in length between the hydrophobic segment of a protein and the hydrophobic thickness of a membrane, a situation that results in energetically unfavorable exposure of hydrophobic protein residues to the hydrophilic environment. to fulfill this definition, a protein must form a channel, and confer mechanically activated currents when expressed heterologously. Further, to be considered a mechanosensor in vivo, the protein must additionally be expressed in mechanosensory cells, and be necessary and sufficient for mechanically activated currents in those cells. the process by which a mechanical stimulus is transduced into biological signals within a cell. the lateral (in-plane) force (N/m) in a membrane bilayer. Membrane tension has been demonstrated to be an activating stimulus for Piezo1 [44Lewis A.H. Grandl J. Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension.Elife. 2015; 4: e12088Crossref PubMed Scopus (191) Google Scholar, 45Cox C.D. et al.Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension.Nat. Commun. 2016; 7: 10366Crossref PubMed Scopus (257) Google Scholar]. specialized skin cell type that is sensitive to light mechanical touch. an ion channel that is activated by multiple distinct stimuli through possibly distinct mechanisms. the sense of one's body position and movement in space. force resulting from the movement of fluid relative to an object (in units of force/cross-sectional area).