Channel complexity
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The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.
- MeSH
- alosterická regulace MeSH
- elektronová kryomikroskopie metody MeSH
- kationtové kanály TRP metabolismus chemie fyziologie MeSH
- kationtový kanál TRPA1 * metabolismus chemie fyziologie MeSH
- lidé MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction with calmodulin (CaM), a cytosol ubiquitous calcium-binding protein. The association between TRPM channels and CaM relies on the presence of specific CaM-binding domains in the channel structure. Upon CaM binding, the channel undergoes direct and/or allosteric structural changes and triggers down- or up-stream signaling pathways. According to current knowledge, ion channel members TRPM2, TRPM3, TRPM4, and TRPM6 are directly modulated by CaM, resulting in their activation or inhibition. This review specifically focuses on the interplay between TRPM channels and CaM and summarizes the current known effects of CaM interactions and modulations on TRPM channels in cellular physiology.
1st ed. 43, 778 s. : il.
- MeSH
- Brugadův syndrom * patofyziologie genetika diagnóza terapie MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- myši MeSH
- napěťově řízený sodíkový kanál, typ 5 genetika MeSH
- sodíkové kanály genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- komentáře MeSH
- úvodníky MeSH
Low-voltage-activated T-type calcium channels are essential contributors to neuronal physiology where they play complex yet fundamentally important roles in shaping intrinsic excitability of nerve cells and neurotransmission. Aberrant neuronal excitability caused by alteration of T-type channel expression has been linked to a number of neuronal disorders including epilepsy, sleep disturbance, autism, and painful chronic neuropathy. Hence, there is increased interest in identifying the cellular mechanisms and actors that underlie the trafficking of T-type channels in normal and pathological conditions. In the present study, we assessed the ability of Stac adaptor proteins to associate with and modulate surface expression of T-type channels. We report the existence of a Cav3.2/Stac1 molecular complex that relies on the binding of Stac1 to the amino-terminal region of the channel. This interaction potently modulates expression of the channel protein at the cell surface resulting in an increased T-type conductance. Altogether, our data establish Stac1 as an important modulator of T-type channel expression and provide new insights into the molecular mechanisms underlying the trafficking of T-type channels to the plasma membrane.
- MeSH
- buněčná membrána metabolismus MeSH
- HEK293 buňky MeSH
- lidé MeSH
- proteiny nervové tkáně metabolismus fyziologie MeSH
- vápníkové kanály - typ T metabolismus fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In contrast to the single-channel dimensional complexity, the global dimensional complexity is calculated from a multichannel EEG. The intention with the method is to measure the spatial distribution of information processing in the brain. The method seems to be of interest in psychopharmacological research, but the interpretation of the results in physiological terms is rather difficult. To get a more detailed information on the physiological significance of the EEG complexity measures, the influence of well-known physiological factors was studied in a group of 14 healthy subjects aged from 1.5 to 61 years. It was found that the correlation dimension was somewhat higher in older individuals, but the correlation with age was not statistically significant. However, the global correlation dimension was significantly lower during full alertness than during drowsiness. These results might reflect the changes in spatial structure of information processing, a high complexity suggesting a 'disorganisation' during drowsiness. As regards the age-dependent changes of the correlation dimension, the spatial 'flexibility' of information processing was also studied, using the differences between the 'alert' and 'drowsy' parts of the same EEG as indicator. It was found that the differences 'drowsy minus alert' were significantly related to age. A plausible interpretation seems to be that the spatial distribution of information processing is more changeable, or more flexible, in adults than in children.
- MeSH
- dítě MeSH
- dospělí MeSH
- elektroencefalografie * statistika a číselné údaje MeSH
- interpretace statistických dat MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mozek * fyziologie MeSH
- pozornost * fyziologie MeSH
- předškolní dítě MeSH
- psychiatrie MeSH
- psychofarmakologie MeSH
- stadia spánku fyziologie MeSH
- věkové faktory MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
Reported findings indicate that attentional narrowing is related to decreased complexity and increased inhibition of neural assemblies. These findings suggest that analysis of electroencephalogram (EEG) complexity could present a useful method for research of attentional changes related to dissociation. To examine this model we used a case study to test the two hypotheses: (1) that successful anticonvulsant medication would result in dissociative symptom alleviation, improvement of inhibitory neural functions, and decreased EEG complexity, and (2) that cognitive conflict, related to aversive events in the patient's past experience, during reliving of a dissociative state would lead to greater allocation of attention and decreased EEG complexity. Three EEG studies recorded in the eyes closed non-drowsy state were performed: (1) at baseline, (2) post-induction of dissociative state, and (3) post-anticonvulsant medication following induction of dissociative state. A dissociative state was achieved following an interview regarding the patient's aversive past experiences through use of the Peritraumatic Dissociative Experiences Questionnaire (PDEQ). The patient's level of dissociation was measured using the Dissociative Experiences Scale-II (DES-II). The PDEQ interview and DES-II assessment were also used one hour following the oral consumption of an anticonvulsant medication (clonazepam 2mg). Analysis of the data revealed that complexity values (PD2) are significantly lower following the oral consumption of clonazepam (2mg) in the majority of EEG channels. Additionally, complexity during the reliving of a dissociative state was statistically significantly lower than both the baseline and post-medication conditions in all but two EEG channels. Results of the case study suggest that changes in attentional processes linked to dissociation are related to: (1) decreased complexity when attention is extremely focused because of attentional narrowing to the disturbing past experience, and (2) increased complexity during ordinary experiences when attention is less narrowly focused.
- MeSH
- antikonvulziva terapeutické užití MeSH
- arousal fyziologie MeSH
- disociační poruchy diagnóza farmakoterapie patofyziologie MeSH
- dospělí MeSH
- elektroencefalografie metody MeSH
- klonazepam terapeutické užití MeSH
- lidé MeSH
- pozornost fyziologie MeSH
- psychometrie MeSH
- úzkostné poruchy diagnóza patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.
- MeSH
- apoptóza účinky léků MeSH
- hexokinasa metabolismus MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mitochondriální membrány účinky léků MeSH
- mitochondrie účinky léků MeSH
- nádorové buněčné linie MeSH
- napětím ovládaný aniontový kanál 1 metabolismus MeSH
- peptidy farmakologie MeSH
- povrchově aktivní látky farmakologie MeSH
- protinádorové látky farmakologie MeSH
- sekvence aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
