Raul Calvo - Academia.edu (original) (raw)
Papers by Raul Calvo
Clinical Image-Based Procedures. Translational Research in Medical Imaging, 2014
Cochlear implantation is a surgical procedure that can restore the hearing capabilities to patien... more Cochlear implantation is a surgical procedure that can restore the hearing capabilities to patients with severe or complete functional loss. However, the level of restoration varies highly between subjects and depends on patient-specific factors. This paper presents a software application for planning cochlear implantation procedures that includes patient-specific anatomy estimation using high resolution models, implant optimization for patient-specific implant selection, simulation of mechanical and electrical properties of the implant as well as clinical reporting.
Mammalian Two-Pore-Channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously-expressed cation channels in... more Mammalian Two-Pore-Channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously-expressed cation channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Lysosomal patch-clamp studies and high-resolution structural determinations have demonstrated that TPCs are Na+-selective channels activated by lysosome-localized PI(3,5)P2. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of several positively-charged amino acid (AA) residues in the presumed "S4 voltage-sensing" domains. By performing a Ca2+-imaging-based high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tri-cyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, so we refer to them as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We...
SSRN Electronic Journal, 2022
Science Translational Medicine, 2020
Innate defense regulator RP-182 targets CD206 high M2-like macrophages in malignant and noncancer... more Innate defense regulator RP-182 targets CD206 high M2-like macrophages in malignant and noncancerous diseases.
Science Advances, 2020
A lysosome activator ameliorates muscular dystrophies.
eLife, 2019
Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activa... more Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed ‘S4 voltage-sensing’ domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies...
Developmental cell, May 8, 2017
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich t... more Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca(2+) imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca(2+) release from TV stores. Hence, we demonstrated that ML1, acting as a Ca(2+) channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca(2+)-dependent TV e...
Nature Communications, 2016
Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'h... more Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'host' multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca 2 þ-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca 2 þ release. This activation triggers calcineurin-dependent TFEB-nuclear translocation, autophagy induction and lysosome biogenesis. When TRPML1 is genetically inactivated or pharmacologically inhibited, clearance of damaged mitochondria and removal of excess ROS are blocked. Furthermore, TRPML1's ROS sensitivity is specifically required for lysosome adaptation to mitochondrial damage. Hence, TRPML1 is a ROS sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback programme to mitigate oxidative stress in the cell.
![Research paper thumbnail of Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (mavatrep)](https://attachments.academia-assets.com/92300736/thumbnails/1.jpg)
](Journal of medicinal chemistry, Jan 8, 2015
Reported herein is the design, synthesis and pharmacologic characterization of a class of TRPV1 a... more Reported herein is the design, synthesis and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzimidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl head group attached to the benzimidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay using cells expressing recombinant human TRPV1 channels, 4 exhibited an IC50 value of 4.7 nM. In a complete Freund's adjuvant-induced thermal hypersensitivity model, 4 exhibited an ED80 value of 7.8 mg/kg, corresponding to plasma levels of 270.8 ng/mL. In a carrageenan-induced thermal hypersensitivity model, 4 reversed thermal hyperalgesia with an ED80 value of 0.5 mg/kg, corresponding to plasma levels of 9.2 ng/mL. Based on its superior pharmacologic and safety profile, 4 (JNJ-3...
Clinical Image-Based Procedures. Translational Research in Medical Imaging, 2014
Cochlear implantation is a surgical procedure that can restore the hearing capabilities to patien... more Cochlear implantation is a surgical procedure that can restore the hearing capabilities to patients with severe or complete functional loss. However, the level of restoration varies highly between subjects and depends on patient-specific factors. This paper presents a software application for planning cochlear implantation procedures that includes patient-specific anatomy estimation using high resolution models, implant optimization for patient-specific implant selection, simulation of mechanical and electrical properties of the implant as well as clinical reporting.
Mammalian Two-Pore-Channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously-expressed cation channels in... more Mammalian Two-Pore-Channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously-expressed cation channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Lysosomal patch-clamp studies and high-resolution structural determinations have demonstrated that TPCs are Na+-selective channels activated by lysosome-localized PI(3,5)P2. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of several positively-charged amino acid (AA) residues in the presumed "S4 voltage-sensing" domains. By performing a Ca2+-imaging-based high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tri-cyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, so we refer to them as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We...
SSRN Electronic Journal, 2022
Science Translational Medicine, 2020
Innate defense regulator RP-182 targets CD206 high M2-like macrophages in malignant and noncancer... more Innate defense regulator RP-182 targets CD206 high M2-like macrophages in malignant and noncancerous diseases.
Science Advances, 2020
A lysosome activator ameliorates muscular dystrophies.
eLife, 2019
Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activa... more Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed ‘S4 voltage-sensing’ domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies...
Developmental cell, May 8, 2017
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich t... more Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca(2+) imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca(2+) release from TV stores. Hence, we demonstrated that ML1, acting as a Ca(2+) channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca(2+)-dependent TV e...
Nature Communications, 2016
Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'h... more Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'host' multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca 2 þ-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca 2 þ release. This activation triggers calcineurin-dependent TFEB-nuclear translocation, autophagy induction and lysosome biogenesis. When TRPML1 is genetically inactivated or pharmacologically inhibited, clearance of damaged mitochondria and removal of excess ROS are blocked. Furthermore, TRPML1's ROS sensitivity is specifically required for lysosome adaptation to mitochondrial damage. Hence, TRPML1 is a ROS sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback programme to mitigate oxidative stress in the cell.
Journal of medicinal chemistry, Jan 8, 2015
Reported herein is the design, synthesis and pharmacologic characterization of a class of TRPV1 a... more Reported herein is the design, synthesis and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzimidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl head group attached to the benzimidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay using cells expressing recombinant human TRPV1 channels, 4 exhibited an IC50 value of 4.7 nM. In a complete Freund's adjuvant-induced thermal hypersensitivity model, 4 exhibited an ED80 value of 7.8 mg/kg, corresponding to plasma levels of 270.8 ng/mL. In a carrageenan-induced thermal hypersensitivity model, 4 reversed thermal hyperalgesia with an ED80 value of 0.5 mg/kg, corresponding to plasma levels of 9.2 ng/mL. Based on its superior pharmacologic and safety profile, 4 (JNJ-3...