Jayanti Mathur's research while affiliated with Genomics Institute of the Novartis Research Foundation and other places

Publications (26)

Article
Mechanotransduction plays a crucial role in vascular biology. One example of this is local regulation of vascular resistance via flow-mediated vasodilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction, and a precursor to a wide array of vascular diseases such as hypertension and atherosclerosis. And yet, the molecules...
Article
Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules respo...
Article
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The volume-regulated anion channel (VRAC) is activated when a cell swells, and it plays a central role in maintaining cell volume in response to osmotic challenges. SWELL1 (LRRC8A) was recently identified as an essential component of VRAC. However, the identity of the pore-forming subunits of VRAC and how the channel is gated by cell swelling are u...
Article
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Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of func...
Article
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Piezo1 and Piezo2 encode mechanically activated cation channels that function as mechanotransducers involved in vascular system development and touch sensing, respectively. Structural features of Piezos remain unknown. Mouse Piezo1 is bioinformatically predicted to have 30-40 transmembrane (TM) domains. Here, we find that nine of the putative inter...
Article
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Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subuni...
Article
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The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion ch...
Article
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Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these...
Article
Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and...
Article
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Dehydrated hereditary stomatocytosis is a genetic condition with defective red blood cell membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations in the mechanically activated PIEZO1 (FAM38A) ion channel were associated with dehydrated hereditary stomatocytosis. However, it is not known...
Article
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Mechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct P...
Article
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Heightened nociceptor function caused by inflammatory mediators such as bradykinin (BK) contributes to increased pain sensitivity (hyperalgesia) to noxious mechanical and thermal stimuli. Although it is known that sensitization of the heat transducer TRPV1 largely subserves thermal hyperalgesia, the cellular mechanisms underlying mechanical hyperal...
Article
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Mechanotransduction has an important role in physiology. Biological processes including sensing touch and sound waves require as-yet-unidentified cation channels that detect pressure. Mouse Piezo1 (MmPiezo1) and MmPiezo2 (also called Fam38a and Fam38b, respectively) induce mechanically activated cationic currents in cells; however, it is unknown wh...
Article
Intracellular Ca(2+) is essential for diverse cellular functions. Ca(2+) entry into many cell types including immune cells is triggered by depleting endoplasmic reticulum (ER) Ca(2+), a process termed store-operated Ca(2+) entry (SOCE). STIM1 is an ER Ca(2+) sensor. Upon Ca(2+) store depletion, STIM1 clusters at ER-plasma membrane junctions where i...
Article
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Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells, but the responsible molecules have not been identified. We characterized a rapidly adapting MA current in a mouse neuroblastoma cel...
Article
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Maintaining physiological pH is required for survival, and exposure to alkaline chemicals such as ammonia (smelling salts) elicits severe pain and inflammation through unknown mechanisms. TRPV1, the capsaicin receptor, is an integrator of noxious stimuli including heat and extracellular acidic pH. Here, we report that ammonia activates TRPV1, TRPA1...
Article
ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling; however, it is unclear whether either ion channel is required for thermosensation in vivo. We show that mice lacking TRPM8 have severe behavioral deficits in response t...
Article
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Menthol is a cooling compound derived from mint leaves and is extensively used as a flavoring chemical. Menthol activates transient receptor potential melastatin 8 (TRPM8), an ion channel also activated by cold, voltage and phosphatidylinositol-4,5-bisphosphate (PIP2). Here we investigated the mechanism by which menthol activates mouse TRPM8. Using...

Citations

... We next sought to establish whether PIEZO1 is functional in somatosensory neurons. Unlike PIEZO2, which to date has no known chemical activators, PIEZO1 can be activated in vitro and in vivo using the small molecule Yoda1, which sensitizes PIEZO1 currents elicited by mechanical stimuli and triggers calcium influx on its own 26 . To assess the effects of Yoda1 on sensory neuron physiology, we turned to ratiometric calcium imaging in dissociated cultured mouse DRG neurons. ...
... Moreover, using stretchable membranes, authors identified that cell stretch also activates OGR1 signaling, which is blunted if actin polymerization is inhibited. These results are in agreement with in vivo experiments performed by another group, in which shear stress was shown to activate OGR1 in mouse endothelial cells [147]. In this study, OGR1 was mainly found in small diameter arterioles of different organs like the intestine, brain, pancreas, and liver. ...
... These channels are permeable to small ions (e.g., Na + , K + , Ca 2+ , and Cl − ) as well as larger molecules (e.g., ATP) (Ma et al., 2016;Chiu et al., 2018), and it has recently proposed that they should be classified as large-pore channels (Syrjanen et al., 2021) [Structural and functional comparisons between LRRC8 and other large-pore channels are well-summarized in a recent review (Syrjanen et al., 2021).] Hetero-hexameric assembly of LRRC8A and at least one other LRRC8 isoform is needed for the formation of a functional VRAC under physiological conditions (Voss et al., 2014;Syeda et al., 2016). The combination of LRRC8A and other LRRC8 isoforms determines the biophysical properties of VRAC including open probability (Syeda et al., 2016), gating kinetics (Voss et al., 2014;Ullrich et al., 2016), and substrate specificity (Planells-Cases et al., 2015;Gaitán-Peñas et al., 2016;Lutter et al., 2017;Schober et al., 2017;Lahey et al., 2020). ...
... The current amplitude varied with stimulus intensity. However, when endogenous Piezo1 was inactivated by CRISPR/Cas9 technique [69], the mechanically activated currents could not be detected anymore. These data suggested the presence of endogenous mechanically activated currents in native HEK-293 cells, which are mediated by Piezo1 channel. ...
... Specifically, Piezo2 exhibits faster inactivation kinetics than Piezo1, which slows down with depolarization 14,33 . Site-directed mutagenesis of residues L2475 and V2476 in the IH and residues M2493/F2494 in the CTD completely eliminated the inactivation of Piezo1 [34][35][36] . Intriguingly, the mutation of M2493/ F2494 has no effect on the inactivation of Piezo2 34 , indicating that the inactivation mechanisms of Piezo2 and Piezo1 are not the same, which might be an inherent reason for their different inactivation kinetics. ...
... Previous research has reported this receptor regulating exocytosis in human adrenal chromaffin cells [11,12]. Besides, α6β4* nAChRs are highly expressed in dorsal root ganglia neurons, which are involved in pain [13][14][15]. Therefore, α6β4* nAChR has the potential to be developed as an attractive non-opioid therapeutic target for pain. ...
... Early work on the expression of Piezo genes unequivocally demonstrated that Piezo2 transcript is present at high levels in somatosensory neurons and suggested that Piezo1 was expressed at only background levels 3,18 . In response to the publication of several single-cell RNA-seq datasets reporting low but detectable expression of Piezo1 transcript in mouse DRG neurons 7,8,19 (Extended Data Fig. 1), we revisited our previous experiments using single-molecule fluorescence in situ hybridization (smFISH) to more thoroughly characterize the expression of Piezo1 in sensory neurons. ...
... smFISH of sections from a human DRG revealed PIEZO1 transcript in 83.6% of NPPB + neurons ( Fig. 1h and Extended Data Fig. 4a,b), suggestive of a conserved pattern of expression. Using a mouse line that expresses a PIEZO1 tdTomato C-terminal fusion protein 25 , we observed robust expression of PIEZO1 tdTomato in platelet endothelial cell adhesion molecule 1 (PECAM1 + ) vascular endothelial cells of the DRG and trigeminal ganglion capillaries (as expected) 20 , as well as within a subset of neuronal cell bodies and nerve fibres, consistent with the expression of PIEZO1 protein in mouse somatosensory neurons (Fig. 1i-l and Extended Data Fig. 5a-c). ...
... VRAC participates in many physiological and pathological processes, including cell proliferation, apoptosis, stroke, diabetes, and cancer [87,101]. The molecular identity of VRAC remained unknown until 2014 when 2 independent groups identified the family of leucine-rich repeat containing 8 (LRRC8) proteins (also known as Swell) as crucial components of VRAC [90,115]. Besides, other Cl − channels, such as TMEM16A [19,67], TMEM16F [5,67], and bestrophin [34], were all suggested to contribute to I Cl,swell . ...
... Physiological roles of Piezo channels Piezo channels play a vital biological role in mechanotransduction in varying mammalian cell types and are associated with a variety of physiological states. Mutations in Piezos pertinent to severe pathologies in humans also underline the essentiality of these ion channels as molecular sensors required for normal physiological function 38,[51][52][53][54] . It has been confirmed that gain-of-function mutations in Piezo1 are linked to hereditary xerocytosis, while loss-of-function mutations induce lymphatic dysplasia [51][52][53] . ...