The functions and underlying molecular mechanisms of PIEZO channels in nervous system diseases

Abstract

BACKGROUND: Recent studies have demonstrated that mechanotransduction plays a critical role in the pathological processes of neurological disorders. PIEZO channels, as key mechanosensitive ion channels, serve as core mediators in sensing and transducing mechanical signals. However, a systematic review of their specific roles across various neurological diseases is relatively lacking. OBJECTIVE: To explore the roles and molecular mechanisms of PIEZO1 and PIEZO2 channels in central and peripheral nervous system diseases, and to evaluate their potential as therapeutic targets. METHODS: A literature search was conducted in PubMed, Web of Science, CNKI, WanFang, and VIP databases from January 2010 to May 2025. English search terms included 'central nervous system diseases', 'Central Nervous System Disorder', 'CNS Disease', 'CNS Diseases', 'Central Nervous System Disorders', 'neurodegenerative disease', 'Autonomic Nervous System Diseases', 'Brain Diseases', 'Central Nervous System Infections', 'High Pressure Neurological Syndrome', 'Spinal Cord Diseases', 'PIEZO1 Channel', 'PIEZO2 Channel', 'PIEZO Channel'; Chinese search terms included '神经系统疾病', '中枢神经系统疾病', 'PIEZO1', 'PIEZO2', 'PIEZO'. A combination of subject headings and free words was used. Based on inclusion and exclusion criteria, 60 English articles were finally included for systematic analysis and classified by disease type. RESULTS AND CONCLUSION: ①PIEZO1 is highly expressed in glioma and correlates with malignancy and poor prognosis; calcium influx promotes tumor proliferation and remodeling of microenvironment stiffness, driving tumor progression. ②In intracerebral hemorrhage, activation of neuronal PIEZO2 promotes iron transporter expression, increases intracellular iron accumulation, induces ferroptosis, and exacerbates secondary brain injury, while PIEZO1 dysfunction impairs cerebrovascular integrity and the blood-brain barrier. ③In traumatic brain injury, upregulation of PIEZO2 in neurons promotes neuronal death and pro-inflammatory cytokine release. ④Activation of PIEZO1 promotes fluid excretion in the brain, alleviating hydrocephalus. ⑤PIEZO1 dysfunction is involved in amyloid-beta toxicity, glial activation, vascular damage, and metabolic abnormalities in Alzheimer's disease. ⑥PIEZO1 activation inhibits myelination and modulates immune responses in multiple sclerosis. ⑦PIEZO1 mediates pulsatile pain characteristic of migraine induced by blood flow pulsation. ⑧Elevated intraocular pressure upregulates PIEZO1 and PIEZO2, leading to hyperexcitability and metabolic stress injury of retinal ganglion cells. ⑨PIEZO channels regulate neuronal excitability, proprioception, and baroreflex abnormalities in amyotrophic lateral sclerosis, and targeting PIEZO is a potential therapeutic strategy.

1. Introduction

Currently, central nervous system diseases (such as stroke and glioma) and neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease) affect millions of people worldwide [1], but the pathogenic mechanisms are not fully understood. In the past decade, extensive research has focused on the biomechanical properties of the central nervous system. Studies have found that mechanical forces acting on the nervous system drive the occurrence of various pathological states [2]. For example, mechanical forces on the cell membrane can directly activate related transduction ion channels, converting mechanical signals into biological signals, thereby enabling the body to respond rapidly to cell membrane excitation or intracellular signal activation [3]. If the function of these ion channels is abnormal, it will have a certain impact on the corresponding nervous system.

PIEZO channels are mechanosensitive ion channels located on the cell membrane, with two members in vertebrates: PIEZO1 and PIEZO2. They are composed of more than 2,500 amino acids, have 24-36 predicted transmembrane segments, and share no sequence homology with other known ion channels. As key cellular mechanotransducers [4], PIEZO channels have pressure-activated properties [5] and can convert mechanical stimuli into electrochemical signals [6]. PIEZO channels form homotrimeric structures that open upon mechanical stimulation [7-8], allowing cations such as Ca2+ and Na+ to cross the cell membrane, enabling cells to sense changes in their microenvironment [9-10]. PIEZO1 is widely expressed in various cell types and participates in physiological processes such as vascular development, erythrocyte volume regulation, and bone remodeling; PIEZO2 is mainly distributed in sensory neurons, mediating tactile, proprioceptive, and pain sensations. The specific mechanisms are shown in Figure 1. However, current research on the role of PIEZO channels in neurological diseases is relatively scarce, and there is no systematic review stratified by disease type, which represents a gap in the clinical application of PIEZO channels.

This review searched and screened studies on PIEZO channels from the past 15 years, classified them by disease type, and discussed the roles of PIEZO1 and PIEZO2 channels in various neurological diseases at the molecular level.