Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

Prestin-Mediated Frequency Selectivity Does not Cover Ultrahigh Frequencies in Mice / 神经科学通报·英文版

In mammals, the piezoelectric protein, Prestin, endows the outer hair cells (OHCs) with electromotility (eM), which confers the capacity to change cellular length in response to alterations in membrane potential. Together with basilar membrane resonance and possible stereociliary motility, Prestin-based OHC eM lays the foundation for enhancing cochlear sensitivity and frequency selectivity. However, it remains debatable whether Prestin contributes to ultrahigh-frequency hearing due to the intrinsic nature of the cell's low-pass features. The low-pass property of mouse OHC eM is based on the finding that eM magnitude dissipates within the frequency bandwidth of human speech. In this study, we examined the role of Prestin in sensing broad-range frequencies (4-80 kHz) in mice that use ultrasonic hearing and vocalization (to >100 kHz) for social communication. The audiometric measurements in mice showed that ablation of Prestin did not abolish hearing at frequencies >40 kHz. Acoustic associative behavior tests confirmed that Prestin-knockout mice can learn ultrahigh-frequency sound-coupled tasks, similar to control mice. Ex vivo cochlear Ca2+ imaging experiments demonstrated that without Prestin, the OHCs still exhibit ultrahigh-frequency transduction, which in contrast, can be abolished by a universal cation channel blocker, Gadolinium. In vivo salicylate treatment disrupts hearing at frequencies <40 kHz but not ultrahigh-frequency hearing. By pharmacogenetic manipulation, we showed that specific ablation of the OHCs largely abolished hearing at frequencies >40 kHz. These findings demonstrate that cochlear OHCs are the target cells that support ultrahigh-frequency transduction, which does not require Prestin.

Progress of diagnosis and treatment of PIEZO2-related diseases / 国际儿科学杂志

As a basic mechanism of cell function, mechanical transduction plays a key role in human growth and development, physiological and pathological processes.And its molecular mechanism has always been a research hotspot.In recent years, Piezo2 has been identified as a mechanically sensitive cationic channel, which serves as an important component of mechanical transduction participating in regulating and maintaining of respiratory rhythm, bowel movement, cartilage stress, tactile sense and multiple other physiological processes.PIEZO2-related diseases have been reported in recent years before which are characterized by distal joint contracture, scoliosis, low muscular tension, and delayed motor development.In this review, we summarizes the clinical phenotype and progress in diagnosis and possible treatment of PIEZO2-related diseases, hoping to improve the recognition of this disease which is essential for long-term management of patients, and provide ideas for the gene research and development of drug targets.

Changes in expression of Piezo2 in spinal cord neurons in a rat model of bone cancer pain / 中华麻醉学杂志

Objective To evaluate the changes in the expression of Piezo2 in spinal cord neurons in a rat model of bone cancer pain.Methods Sixty-four pathogen-free healthy adult female unmated Sprague-Dawley rats,weighing 160-200 g,were divided into 2 groups (n=32 each) using a random number table:sham operation group (group S) and bone cancer pain group (group BP).Bone cancer pain was induced by injecting breast cancer cells into the abdominal cavity.The mechanical paw withdrawal threshold (MWT) was measured at 1 day before inoculating breast cancer cells and 7,14 and 21 days after inoculation (T0-3).Eight rats were sacrificed after measurement of MWT,and their lumbar enlargement segments of the spinal cord were removed for determination of Piezo2 expression by Western blot and immunofluorescence.The coexpression of Piezo2 with the neuronal marker NeuN,microglial marker Iba-1 and astrocyte marker GFAP was detected at T2 using double immunofluorescent staining.Results Compared with group S,the MWT was significandy decreased at T1-3,and the Piezo2 expression in the lumbar enlargement segment of the spinal cord was up-regulated in group BP (P ＜ 0.05).Piezo2 was mainly expressed in the spinal lamina Ⅰ and Ⅱ and co-expressed with NeuN and rarely co-expressed with GFAP or Iba-1.Conclusion The development and maintenance of bone cancer pain are related to up-regulated expression of Piezo2 in the lumbar enlargement segment of the spinal cord in rats.

Piezo2: A Candidate Biomarker for Visceral Hypersensitivity in Irritable Bowel Syndrome?

BACKGROUND/AIMS: Currently, there exists no biomarker for visceral hypersensitivity in irritable bowel syndrome (IBS). Piezo proteins have been proven to play an important role in the mechanical stimulation to induce visceral pain in other tissues and may also be a biomarker candidate. The aim of this study was to test the expressions of Piezo1 and Piezo2 proteins in the intestinal epithelial cells from different intestinal segments and to explore the correlation between Piezo proteins expression and visceral pain threshold. METHODS: Post-infectious IBS was induced in mice via a Trichinella spiralis infection. Visceral sensitivity was measured with abdominal withdrawal reflex to colorectal distention. Inflammation in the small intestine and colon was scored with H&E staining. Expression location of Piezo proteins was confirmed by immunohistochemistry. Abundance of Piezo proteins were measured with real-time reverse transcriptase polymerase chain reaction. RESULTS: Piezo1 and Piezo2 proteins were expressed in the intestinal epithelial cells. The expression levels of Piezo1 and Piezo2 were abundant in the colon than the small intestine (P < 0.001 for Piezo1, P = 0.003 for Piezo2). Expression of Piezo2 in the colon significantly correlated to the visceral sensitivity (r = −0.718, P = 0.001) rather than the mucosal inflammation. CONCLUSION: Piezo2 is a candidate biomarker for visceral hypersensitivity in IBS.