The transient receptor potential (TRP) channel superfamily consists of a large group of non-selective cation channels that serve as cellular sensors for a wide spectrum of physical and environmental ...stimuli. The 28 mammalian TRPs, categorized into six subfamilies, including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin) and TRPP (polycystin), are widely expressed in different cells and tissues. TRPs exhibit a variety of unique features that not only distinguish them from other superfamilies of ion channels, but also confer diverse physiological functions. Located at the plasma membrane or in the membranes of intracellular organelles, TRPs are the cellular safeguards that sense various cell stresses and environmental stimuli and translate this information into responses at the organismal level. Loss- or gain-of-function mutations of TRPs cause inherited diseases and pathologies in different physiological systems, whereas up- or down-regulation of TRPs is associated with acquired human disorders. In this Cell Science at a Glance article and the accompanying poster, we briefly summarize the history of the discovery of TRPs, their unique features, recent advances in the understanding of TRP activation mechanisms, the structural basis of TRP Ca2+ selectivity and ligand binding, as well as potential roles in mammalian physiology and pathology.
Viral pneumonia (VP) is known for its wide transmission and severe pathological damage. ninety cases of VP patients were rolled into an experimental group (group E, methylprednisolone + advanced ...antibiotics + antiviral drugs) and a control group (group C, methylprednisolone), with 45 cases in each group. General information about the patients, inflammatory factors, serum immunoglobulins, T lymphocyte subsets, and treatment outcomes (efficiency rate, conversion rate to negative) were compared. In group E, interleukin-6 (IL-6) (0.18±0.07) ng/L was inferior to in group C (0.33±0.09) ng/L, p<0.05; tumor necrosis factor-alpha (TNF-α) (17.22±4.13) ng/L was inferior to group C (26.07±4.08) ng/L, p<0.05; lgA (0.81±0.22) g/L was superior to in group C (0.68±0.17) g/L, P<0.05; lgM (1.62±0.13) g/L was superior to group C (1.09±0.03) g/L, p<0.05; lgE (0.19±0.02) g/L was inferior to group C (0.23±0.03) g/L, p<0.05; CD4+/CD8+ ratio (1.71±0.33) was superior to group C (1.24±0.43), p<0.05; the total efficiency rate in group C (77.78%) was inferior to group E (97.78%), p<0.05; the conversion rate to negative of viral antigens in group E (91.11%) was superior to in group C (64.44%), p<0.05. methylprednisolone in combination with advanced antibiotics and antiviral drugs is an effective treatment approach for VP.
Role of TRP channels in the cardiovascular system Yue, Zhichao; Xie, Jia; Yu, Albert S ...
American journal of physiology. Heart and circulatory physiology,
02/2015, Letnik:
308, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be ...grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.
Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in ...clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDAR-induced excitotoxicity is enhanced by physical and functional coupling of NMDAR to an ion channel TRPM2 upon ischemic insults. TRPM2-NMDAR association promotes the surface expression of extrasynaptic NMDARs, leading to enhanced NMDAR activity and increased neuronal death. We identified a specific NMDAR-interacting motif on TRPM2 and designed a membrane-permeable peptide to uncouple the TRPM2-NMDAR interaction. This disrupting peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to mitigate excitotoxic neuronal death without directly targeting NMDARs.
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•TRPM2 physically and functionally interacts with extrasynaptic NMDAR•TRPM2-NMDAR interaction exacerbates excitotoxicity during ischemic stroke•TRPM2 recruits PKCγ, thereby increasing NMDAR’s surface expression•Uncoupling TRPM2-NMDAR interaction attenuates ischemic brain injury
Zong et al. discover an unexpected association between the oxidative stress-sensitive ion channel TRPM2 and the extrasynaptic NMDA receptor (NMDAR) in the neurons, which enhances excitotoxicity during ischemic brain injury. Neuron-specific knockout of TRPM2 or uncoupling of the TRPM2-NMDAR association using an interfering peptide protects mice against ischemic stroke.
Biodegradable Piezoelectric Force Sensor Curry, Eli J.; Ke, Kai; Chorsi, Meysam T. ...
Proceedings of the National Academy of Sciences,
01/2018, Letnik:
115, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Measuring vital physiological pressures is important for monitoring health status, preventing the buildup of dangerous internal forces in impaired organs, and enabling novel approaches of using ...mechanical stimulation for tissue regeneration. Pressure sensors are often required to be implanted and directly integrated with native soft biological systems. Therefore, the devices should be flexible and at the same time biodegradable to avoid invasive removal surgery that can damage directly interfaced tissues. Despite recent achievements in degradable electronic devices, there is still a tremendous need to develop a force sensor which only relies on safe medical materials and requires no complex fabrication process to provide accurate information on important biophysiological forces. Here, we present a strategy for material processing, electromechanical analysis, device fabrication, and assessment of a piezoelectric Poly-L-lactide (PLLA) polymer to create a biodegradable, biocompatible piezoelectric force sensor, which only employs medical materials used commonly in Food and Drug Administration-approved implants, for the monitoring of biological forces. We show the sensor can precisely measure pressures in a wide range of 0–18 kPa and sustain a reliable performance for a period of 4 d in an aqueous environment. We also demonstrate this PLLA piezoelectric sensor can be implanted inside the abdominal cavity of a mouse to monitor the pressure of diaphragmatic contraction. This piezoelectric sensor offers an appealing alternative to present biodegradable electronic devices for the monitoring of intraorgan pressures. The sensor can be integrated with tissues and organs, forming self-sensing bionic systems to enable many exciting applications in regenerative medicine, drug delivery, and medical devices.
Melastatin-related transient receptor potential channel 2 (TRPM2) is a Ca²⁺-permeable, nonselective cation channel that is involved in oxidative stress-induced cell death and inflammation processes. ...Although TRPM2 can be activated by ADP-ribose (ADPR) in vitro, it was unknown how TRPM2 is gated in vivo. Moreover, several alternative spliced isoforms of TRPM2 identified recently are insensitive to ADPR, and their gating mechanisms remain unclear. Here, we report that intracellular Ca²⁺ (Ca²⁺i) can activate TRPM2 as well as its spliced isoforms. We demonstrate that TRPM2 mutants with disrupted ADPR-binding sites can be activated readily by Ca²⁺i, indicating that Ca²⁺i gating of TRPM2 is independent of ADPR. The mechanism by which Ca²⁺i activates TRPM2 is via a calmodulin (CaM)-binding domain in the N terminus of TRPM2. Whereas Ca²⁺-mediated TRPM2 activation is independent of ADPR and ADPR-binding sites, both Ca²⁺i and the CaM-binding motif are required for ADPR-mediated TRPM2 gating. Importantly, we demonstrate that intracellular Ca²⁺ release activates both recombinant and endogenous TRPM2 in intact cells. Moreover, receptor activation-induced Ca²⁺ release is capable of activating TRPM2. These results indicate that Ca²⁺i is a key activator of TRPM2 and the only known activator of the spliced isoforms of TRPM2. Our findings suggest that Ca²⁺i-mediated activation of TRPM2 and its alternative spliced isoforms may represent a major gating mechanism in vivo, therefore conferring important physiological and pathological functions of TRPM2 and its spliced isoforms in response to elevation of Ca²⁺i.
The transient receptor potential melastatin 4 (TRPM4) is a Ca
2+
-activated nonselective monovalent cation channel belonging to the TRP channel superfamily. TRPM4 is widely expressed in various ...tissues and most abundantly expressed in the heart. TRPM4 plays a critical role in cardiac conduction. Patients carrying a gain-of-function or loss-of-function mutation of TRPM4 display impaired cardiac conduction. Knockout or over-expression of TRPM4 in mice recapitulates conduction defects in patients. Moreover, recent studies have indicated that TRPM4 plays a role in hypertrophy and heart failure. Whereas the role of TRPM4 mediated by cardiac myocytes has been well investigated, little is known about TRPM4 and its role in cardiac fibroblasts. Here we show that in human left ventricular fibroblasts, TRPM4 exhibits typical Ca
2+
-activation characteristics, linear current–voltage (I–V) relation, and monovalent permeability. TRPM4 currents recorded in fibroblasts from heart failure patients (HF) are more than 2-fold bigger than those from control individuals (CTL). The enhanced functional TRPM4 in HF is not resulted from changed channel properties, as TRPM4 currents from both HF and CTL fibroblasts demonstrate similar sensitivity to intracellular calcium activation and extracellular 9-phenanthrol (9-phen) blockade. Consistent with enhanced TRPM4 activity, the protein level of TRPM4 is about 2-fold higher in HF than that of CTL hearts. Moreover, TRPM4 current in CTL fibroblasts is increased after 24 hours of TGFβ1 treatment, implying that TRPM4
in vivo
may be upregulated by fibrogenesis promotor TGFβ1. The upregulated TRPM4 in HF fibroblasts suggests that TRPM4 may play a role in cardiac fibrogenesis under various pathological conditions.
Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most commonly sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested ...that Ca(2+) signals are involved in fibrosis promotion, the molecular basis of Ca(2+) signaling mechanisms and how Ca(2+) signals contribute to fibrogenesis remain unknown.
To determine the molecular mechanisms of Ca(2+)-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca(2+) signals contribute to fibrogenesis in human AF.
We demonstrate that the transient receptor potential (TRP) melastatin related 7 (TRPM7) is the molecular basis of the major Ca(2+)-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA largely eliminates TRPM7 current and Ca(2+) influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca(2+) influx and are more prone to myofibroblast differentiation, presumably attributable to the enhanced expression of TRPM7. TRPM7 small hairpin RNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor (TGF)-beta1, the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca(2+) signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-beta1-induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-beta1.
Our results establish that TRPM7 is the major Ca(2+)-permeable channel in human atrial fibroblasts and likely plays an essential role in TGF-beta1-elicited fibrogenesis in human AF.
TRPM6 and TRPM7 are two known channel kinases that play important roles in various physiological processes, including Mg2+ homeostasis. Mutations in TRPM6 cause hereditary hypomagnesemia and ...secondary hypocalcemia (HSH). However, whether TRPM6 encodes functional channels is controversial. Here we demonstrate several signature features of TRPM6 that distinguish TRPM6 from TRPM7 and TRPM6/7 channels. We show that heterologous expression of TRPM6 but not the mutant TRPM6(S141L) produces functional channels with divalent cation permeability profile and pH sensitivity distinctive from those of TRPM7 channels and TRPM6/7 complexes. TRPM6 exhibits unique unitary conductance that is 2- and 1.5-fold bigger than that of TRPM7 and TRPM6/7. Moreover, micromolar levels of 2-aminoethoxydiphenyl borate (2-APB) maximally increase TRPM6 but significantly inhibit TRPM7 channel activities; whereas millimolar concentrations of 2-APB potentiate TRPM6/7 and TRPM7 channel activities. Furthermore, Mg2+ and Ca2+ entry through TRPM6 is enhanced three- to fourfold by 2-APB. Collectively, these results indicate that TRPM6 forms functional homomeric channels as well as heteromeric TRPM6/7 complexes. The unique characteristics of these three channel types, TRPM6, TRPM7, and TRPM6/7, suggest that they may play different roles in vivo.
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