Evolution of Transient Receptor Potential (TRP) Ion Channels in Antarctic Fishes (Cryonotothenioidea) and Identification of Putative Thermosensors

Genome Biology and Evolution, Journal Year: 2022, Volume and Issue: 14(2)

Published: Jan. 27, 2022

Abstract Animals rely on their sensory systems to inform them of ecologically relevant environmental variation. In the Southern Ocean, thermal environment has remained between −1.9 and 5 °C for 15 Myr, yet we have no knowledge how an Antarctic marine organism might sense habitat as discover a thermosensitive ion channel that gates (opens/closes) below 10 °C. Here, investigate evolutionary dynamics transient receptor potential (TRP) channels, which are primary thermosensors in animals, within cryonotothenioid fishes—the dominant fish fauna Ocean. We found cryonotothenioids similar complement TRP channels other teleosts (∼28 genes). Previous work shown gating given is species specific, multiple act together environment. Therefore, combined evidence changes selective pressure, gene gain/loss dynamics, first ganglion transcriptome this clade identify best candidate functional dynamic range frigid temperatures. concluded TRPV1a, TRPA1b, TRPM4 likeliest putative thermosensors, diversifying selection at sites across these proteins. also put forward hypotheses molecular mechanisms adaptations, such reduced skeletal calcium deposition, sensing oxidative stress, unusual magnesium homeostasis. By completing comprehensive unbiased survey genes, lay groundwork characterization answering long-standing thermodynamic questions protein adaptation low

Language: Английский

---

Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(6), P. 1806 - 1818

Published: Feb. 6, 2023

Commonly used techniques, such as CryoEM or X-ray, are not able to capture the structural reorganizations of disordered regions proteins (IDR); therefore, it is difficult assess their functions in based exclusively on experiments. To fill this gap, we computational molecular dynamics (MD) simulation methods IDR and trace biological function-related interactions Kir6.2/SUR1 potassium channel. This ATP-sensitive octameric complex, one critical elements insulin secretion process human pancreatic β-cells, has four five large, fragments. Using unique MD simulations full channel present an in-depth analysis discuss possible they could have system. Our results confirmed crucial role N-terminus Kir6.2 fragment L0-loop SUR1 protein transfer mechanical signals between domains that trigger release. Moreover, show presence IDRs affects natural ligand binding. research takes us step further toward understanding action vital complex.

Language: Английский

---

Synergistic Responses Conferred by Concurrent Optical and Magnetic Stimulation are Attenuated by Simultaneous Exposure to Streptomycin: An Aminoglycoside Antibiotic Dilemma

Published: June 7, 2024

Concurrent Optical and Magnetic Stimulation (COMS) combines extremely low frequency electromagnetic light stimulation modalities for enhanced wound healing. In this report, we investigated the potential mechanistic synergism between magnetic components by comparing their individual combined cellular responses. Although each mode was capable of stimulating cell proliferation, fields exposure alone produced greater proliferation enhancement than alone, yet effects were supra-additive Reactive oxygen species incrementally reduced to light, magnetics combination, where statistical significance ultimately achieved. On other hand, ATP production significantly in response or combination with light. These results suggest that mitochondrial respiratory efficiency preferentially improved two stimuli. Protein expression related combinatory COMS modality as protein levels TRPC1 cation channel previously implicated part a calcium-mitochondrial signaling axis invoked involved proliferation. corroborate facilitates functional impinge on mitochondria-dependent developmental The aminoglycoside antibiotics (AGAs) have been shown antagonize TRPC1-mediated magnetotransduction. Streptomycin applied during any modes enhancement, whereas streptomycin added after did not. Notably, field partially overcoming antagonism Transductional combinatorial photon-electromagnetic thus aligns previous studies showing AGAs block magnetotransduction when exposure. prophylactic usage (neomycin) should be avoided therapy maintain clinical efficacy would common concern most regenerative paradigms.

Language: Английский

---

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants

Brain, Journal Year: 2024, Volume and Issue: 148(2), P. 564 - 579

Published: July 18, 2024

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias arthropathy. Pathogenic gain function toxicity that can be rescued by small molecule antagonists cellular animal models, suggesting antagonism could therapeutic for patients. Numerous variants have been detected with targeted whole exome/genome sequencing, but vast majority, their pathogenicity remains unclear. Here, we used a combination clinical information experimental structure-function analyses to evaluate 30 across various functional protein domains. We report features seven patients unknown significance provide extensive characterization these an additional 17 variants, structural position, function, subcellular localization, expression level, cytotoxicity protein-protein interactions. find gain-of-function within intracellular ankyrin repeat domain target charged amino acid residues important RhoA interaction, whereas outside interface normal or reduced activity. further identify cluster intrinsically disordered region may via altered interactions membrane lipids. In contrast, assessed transmembrane other regions do not are likely benign. Clinical associated include congenital onset vocal cord weakness motor-predominant benign often demonstrated late-onset sensory-predominant disease. These results framework assessing respect pathogenicity, which will yield critical inform patient selection future trials channelopathies.

Language: Английский

---

Synergistic Cellular Responses Conferred by Concurrent Optical and Magnetic Stimulation Are Attenuated by Simultaneous Exposure to Streptomycin: An Antibiotic Dilemma

Bioengineering, Journal Year: 2024, Volume and Issue: 11(7), P. 637 - 637

Published: June 21, 2024

Concurrent optical and magnetic stimulation (COMS) combines extremely low-frequency electromagnetic light exposure for enhanced wound healing. We investigated the potential mechanistic synergism between components of COMS by comparing their individual combined cellular responses. Lone field produced greater enhancements in cell proliferation than alone, yet effects fields were supra-additive Reactive oxygen species incrementally reduced to light, magnetics fields, combination, wherein statistical significance was only achieved modality. By contrast, ATP production most greatly combination with indicating that mitochondrial respiratory efficiency improved plus light. Protein expression pertaining preferentially modality, as protein levels TRPC1 cation channel had been previously implicated part a calcium–mitochondrial signaling axis invoked necessary proliferation. These results indicate facilitates functional ultimately impinge on mitochondria-dependent developmental Aminoglycoside antibiotics (AGAs) have shown inhibit TRPC1-mediated magnetotransduction, whereas influence over photomodulation has not explored. Streptomycin applied during or respective enhancements, streptomycin added after did not. Magnetic modality capable partially overcoming antagonism treatment, alone The photon-electromagnetic implicates calcium entry both magnetotransduction photomodulation. Avoiding prophylactic use AGAs therapy will be crucial maintaining clinical efficacy is common concern other regenerative paradigms.

Language: Английский

---

Are Aminoglycoside Antibiotics TRPing Your Metabolic Switches?

Cells, Journal Year: 2024, Volume and Issue: 13(15), P. 1273 - 1273

Published: July 29, 2024

Transient receptor potential (TRP) channels are broadly implicated in the developmental programs of most tissues. Amongst these tissues, skeletal muscle and adipose noteworthy for being essential establishing systemic metabolic balance. TRP respond to environmental stimuli by supplying intracellular calcium that instigates enzymatic cascades consequence often impinge on mitochondrial function biogenesis. Critically, aminoglycoside antibiotics (AGAs) have been shown block capacity conduct entry into cell response a wide range biophysical nature, including mechanical, electromagnetic, thermal, chemical. Paradoxically, vitro paradigms commonly used understand organismal development may led astray conventional use streptomycin, an AGA, help prevent bacterial contamination. Accordingly, streptomycin has disrupt both vivo myogenesis, as well phenotypic switch white beige thermogenic status. In vivo, TRP-mediated calcium-dependent exercise adaptations importance metabolism. Alternatively, also curb detrimental levels leakage dystrophic through aberrantly gated TRPC1 be involved etiology X-linked muscular dystrophies. susceptible AGA antagonism critically modulating tissues that, if administered behaving animals, translate systemwide disruption. Regenerative medicine clinical communities need made aware this caveat usage seek viable alternatives, contamination or infection paradigms, respectively.

Language: Английский

---

Multiubiquitination of TRPV4 reduces channel activity independent of surface localization

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(4), P. 101826 - 101826

Published: March 14, 2022

Ubiquitin (Ub)-mediated regulation of plasmalemmal ion channel activity canonically occurs via stimulation endocytosis. Whether ubiquitination can modulate by alternative mechanisms remains unknown. Here, we show that the transient receptor potential vanilloid 4 (TRPV4) cation is multiubiquitinated within its cytosolic N-terminal and C-terminal intrinsically disordered regions (IDRs). Mutagenizing select lysine residues to block but not IDR resulted in a marked elevation TRPV4-mediated intracellular calcium influx, without increasing cell surface expression levels. Conversely, enhancing TRPV4 an E3 Ub ligase reduced did decrease plasma membrane abundance. These results demonstrate Ub-dependent function independent effects on localization. Consistent with playing key negative modulatory role channel, gain-of-function neuropathy-causing mutations gene led both cellular Drosophila models neuropathy, whereas mutant partially suppressed overactivity. Together, these data reveal novel mechanism which flexible domain modulates independently endocytic trafficking identify contributory for this pathway dysregulation mutations.

Language: Английский

---

Lighting up Nobel Prize-winning studies with protein intrinsic disorder

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(8)

Published: July 26, 2022

Language: Английский

---

Regulation of ThermoTRP Channels by PIP2 and Cholesterol

Advances in experimental medicine and biology, Journal Year: 2023, Volume and Issue: unknown, P. 245 - 277

Published: Jan. 1, 2023

Language: Английский

---

Sensory neuron transcriptomes reveal complex neuron-specific function and regulation of mec-2/Stomatin splicing

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 50(5), P. 2401 - 2416

Published: Nov. 10, 2021

The function and identity of a cell is shaped by transcription factors controlling transcriptional networks, further RNA binding proteins post-transcriptional networks. To overcome limitations inherent to analysis sparse single-cell data, we leverage the invariant Caenorhabditis elegans lineage, isolating thousands identical neuron types from isogenic individuals. resulting deep transcriptomes facilitate splicing network due increased sequencing depth uniformity. We focus on mechanosensory touch-neuron regulated MEC-8/RBPMS. identify small MEC-8-regulated network, where MEC-8 establishes isoforms differing default found in other cells. canonical long mec-2/Stomatin isoform touch neurons, but surprisingly non-canonical short predominates including olfactory mec-2 required for olfaction. Forced endogenous isoform-specific expression reveals that functions olfaction not mechanosensation. functional both processes. Remarkably, restoring completely rescues mec-8 mutant mechanosensation, indicating single target phenotypically relevant. Within cassette exon diversifying into long/extra-long isoforms. Neither sufficient Both are simultaneously required, likely functioning as heteromers mediate

Language: Английский

---