Mechanosensation is the biological process by which living cells perceive and respond to physical forces from their environment, such as pressure, stretch, or fluid flow. This ability governs everything from simple reflexes to complex physiological processes. For decades, the specific molecules responsible for translating these physical movements into electrochemical signals remained largely a mystery. A family of proteins known as Piezo, derived from the Greek word píesi meaning pressure, was finally identified as the molecular machinery that allows mammalian cells to sense these mechanical inputs. These membrane-spanning ion channels form the core of the body’s pressure-sensing system, linking physical sensation to cellular communication.
Identifying Piezo One and Two
The discovery of the Piezo family was a significant breakthrough in sensory biology, led by Ardem Patapoutian’s laboratory in 2010. Researchers systematically searched for genes that conferred a mechanically activated electrical current to cells otherwise insensitive to physical touch. This genetic screen identified the first member, Piezo1, and soon after, a closely related protein, Piezo2.
Vertebrates possess these two main isoforms, which show approximately 40% similarity in their amino acid sequences but have distinct roles and tissue distributions. Piezo1 is broadly expressed across many non-sensory tissues, including the liver, lungs, bladder, endothelial cells lining blood vessels, and red blood cells. Conversely, Piezo2 is predominantly found in sensory structures, such as dorsal root ganglia neurons and Merkel cells in the skin. This differential localization suggests a division of labor: Piezo1 generally mediates internal mechanosensation, while Piezo2 specializes in external touch and body position awareness.
How Mechanical Force Generates Signals
Piezo proteins have a unique architecture directly tied to their function as mechanical sensors. The full protein complex is a trimeric structure that resembles a three-bladed propeller embedded within the cell membrane. Each of the three subunits contributes to a dome-like structure that curves the surrounding lipid membrane.
This structural footprint allows the protein to act as a tension sensor within the membrane. When a mechanical force, such as stretching or poking, is applied to the cell, the tension in the surrounding lipid membrane increases. This increase causes a rapid conformational change in the Piezo protein, essentially flattening the propeller-like blades.
The flattening motion is transmitted through a lever-like mechanism to the center of the structure, where the ion-conducting pore is located. The pore, which is normally closed, quickly opens in response to this force, allowing a rapid influx of positively charged ions, primarily calcium, into the cell. This flow of charge converts the physical force into a detectable electrical or chemical signal, a process known as mechanotransduction. The channel then rapidly closes, or inactivates, even if the mechanical stimulus is sustained.
Piezo Proteins and Fundamental Senses
The signals generated by Piezo proteins orchestrate a diverse array of physiological functions. Piezo2 is the main sensor for proprioception, the body’s unconscious sense of its own position and movement in space. Found in nerve endings in muscles and tendons, Piezo2 detects the degree of muscle stretch and joint angle, allowing for coordinated movement and balance.
In the skin, Piezo2-expressing neurons and Merkel cells are responsible for the sensation of light touch. This sensitivity allows the detection of gentle stimuli, such as a whisper of air or the brush of clothing. Piezo2 is also involved in aspects of pain perception, or nociception, particularly mechanical hypersensitivity.
Piezo1 plays a non-sensory role in regulating the internal environment. In the endothelium lining blood vessels, Piezo1 channels sense the shear stress generated by blood flow. When blood flows faster, the increased force opens Piezo1, leading to a calcium influx that helps the vessel widen, regulating vascular tone and blood pressure. Piezo1 is also active in red blood cells, where it senses changes in cell volume and membrane tension. It helps regulate the flow of ions and water, which maintains the cell’s shape and hydration as it navigates the circulatory system.
Clinical Relevance of Piezo Dysfunction
Genetic mutations that alter the function of Piezo channels are linked to several human diseases. Gain-of-function mutations in the PIEZO1 gene, where the channel stays open for too long, cause Hereditary Xerocytosis. This condition is a form of hemolytic anemia where red blood cells lose water and become dehydrated, leading to their premature destruction.
Conversely, loss-of-function mutations in PIEZO1, where channel activity is reduced, have been implicated in Generalized Lymphatic Dysplasia. This disorder affects the lymphatic system’s development, often resulting in fluid accumulation, such as fetal hydrops, due to impaired lymphatic vessel function.
Mutations in PIEZO2 primarily affect the nervous system’s ability to process mechanical stimuli. Humans with loss-of-function PIEZO2 mutations exhibit severe deficits in proprioception, leading to uncoordinated movements and difficulty sensing limb position without visual input. These individuals also show a diminished ability to detect light touch. Understanding these mechanisms offers new paths for treatment, such as developing specific Piezo2 antagonists to reduce chronic mechanical pain or allodynia.