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Biochemistry. Biokhimiia Oct 2023Channelrhodopsins stand out among other retinal proteins because of their capacity to generate passive ionic currents following photoactivation. Owing to that,... (Review)
Review
Channelrhodopsins stand out among other retinal proteins because of their capacity to generate passive ionic currents following photoactivation. Owing to that, channelrhodopsins are widely used in neuroscience and cardiology as instruments for optogenetic manipulation of the activity of excitable cells. Photocurrents generated by channelrhodopsins were first discovered in the cells of green algae in the 1970s. In this review we describe this discovery and discuss the current state of research in the field.
Topics: Channelrhodopsins; Optogenetics; Phototaxis; Light; Ion Transport
PubMed: 38105024
DOI: 10.1134/S0006297923100115 -
The EMBO Journal Jul 2023There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling...
There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na /Ca signature required for persistent invasion. We identify the Na leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca oscillations required for invadopodia formation. Indeed, NALCN-mediated Na influx into cancer cells maintains intracellular Ca oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na /Ca exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.
Topics: Male; Humans; Sodium; Ion Channels; Ion Transport; Prostatic Neoplasms; Membrane Proteins
PubMed: 37278161
DOI: 10.15252/embj.2022112198 -
Bioscience Reports May 2024Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in... (Review)
Review
Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.
Topics: Humans; Chlorides; Animals; Homeostasis; Chloride Channels; Signal Transduction; Extracellular Fluid; Ion Transport
PubMed: 38573803
DOI: 10.1042/BSR20240029 -
Nature Structural & Molecular Biology Jul 2023Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have...
Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have general universal features. However, elucidation of such mechanisms is a challenge. It requires true-atomic-resolution structures of all key proton-conducting states. Here we present a comprehensive function-structure study of a light-driven bacterial inward proton pump, xenorhodopsin, from Bacillus coahuilensis in all major proton-conducting states. The structures reveal that proton translocation is based on proton wires regulated by internal gates. The wires serve as both selectivity filters and translocation pathways for protons. The cumulative results suggest a general concept of proton translocation. We demonstrate the use of serial time-resolved crystallography at a synchrotron source with sub-millisecond resolution for rhodopsin studies, opening the door for principally new applications. The results might also be of interest for optogenetics since xenorhodopsins are the only alternative tools to fire neurons.
Topics: Protons; Proton Pumps; Ion Transport
PubMed: 37386213
DOI: 10.1038/s41594-023-01020-9 -
International Journal of Molecular... Oct 2023Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial... (Review)
Review
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.
Topics: Calmodulin; TRPM Cation Channels; Calcium-Binding Proteins; Calcium Signaling; Protein Binding; Calcium
PubMed: 37894842
DOI: 10.3390/ijms242015162 -
Current Opinion in Plant Biology Feb 2024Calcium (Ca) signaling consists of three steps: (1) initiation of a change in cellular Ca concentration in response to a stimulus, (2) recognition of the change through... (Review)
Review
Calcium (Ca) signaling consists of three steps: (1) initiation of a change in cellular Ca concentration in response to a stimulus, (2) recognition of the change through direct binding of Ca by its sensors, (3) transduction of the signal to elicit downstream responses. Recent studies have uncovered a central role for Ca signaling in both layers of immune responses initiated by plasma membrane (PM) and intracellular receptors, respectively. These advances in our understanding are attributed to several lines of research, including invention of genetically-encoded Ca reporters for the recording of intracellular Ca signals, identification of Ca channels and their gating mechanisms, and functional analysis of Ca binding proteins (Ca sensors). This review analyzes the recent literature that illustrates the importance of Ca homeostasis and signaling in plant innate immunity, featuring intricate Cadependent positive and negative regulations.
Topics: Calcium; Plant Immunity; Signal Transduction; Homeostasis; Calcium Signaling
PubMed: 38043138
DOI: 10.1016/j.pbi.2023.102485 -
Science Signaling Nov 2023Humans and mice with mutations in and manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in at amino acid 1344 () exhibit...
Humans and mice with mutations in and manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in at amino acid 1344 () exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Furthermore, we found that dysregulation of membrane potential was associated with impaired Ca-dependent activation of large-conductance Ca-activated K (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca signaling. mutations impair protein folding, which can cause SR stress. Treating mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca signaling, maintained BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICHs. We conclude that alterations in SR Ca handling that impair ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone and contribute to age-related cSVD in mice.
Topics: Mice; Animals; Humans; Signal Transduction; Ion Transport; Vasoconstriction; TRPM Cation Channels; Collagen Type IV
PubMed: 37963192
DOI: 10.1126/scisignal.adi3966 -
Biochimica Et Biophysica Acta.... Jun 2024The myotubularin family, encompassing myotubularin 1 (MTM1) and 14 myotubularin-related proteins (MTMRs), represents a conserved group of phosphatases featuring a... (Review)
Review
The myotubularin family, encompassing myotubularin 1 (MTM1) and 14 myotubularin-related proteins (MTMRs), represents a conserved group of phosphatases featuring a protein tyrosine phosphatase domain. Nine members are characterized by an active phosphatase domain C(X)R, dephosphorylating the D3 position of PtdIns(3)P and PtdIns(3,5)P2. Mutations in myotubularin genes result in human myopathies, and several neuropathies including X-linked myotubular myopathy and Charcot-Marie-Tooth type 4B. MTM1, MTMR6 and MTMR14 also contribute to Ca signaling and Ca homeostasis that play a key role in many MTM-dependent myopathies and neuropathies. Here we explore the evolving roles of MTM1/MTMRs, unveiling their influence on critical aspects of Ca signaling pathways.
Topics: Humans; Protein Tyrosine Phosphatases, Non-Receptor; Calcium; Homeostasis; Calcium Signaling; Animals; Myopathies, Structural, Congenital; Mutation
PubMed: 38710289
DOI: 10.1016/j.bbamcr.2024.119739 -
Biomedicine & Pharmacotherapy =... Jun 2024The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular... (Review)
Review
The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular homeostasis is disrupted, ER quality control (ERQC) system is activated effectively to remove misfolded and unfolded proteins through ER-phagy, ER-related degradation (ERAD), and molecular chaperones. When unfolded protein response (UPR) and ER stress are activated, the cell may be suffering a huge blow, and the most probable consequence is apoptosis. The membrane contact points between the ER and sub-organelles contribute to communication between the organelles. The decrease in oxygen concentration affects the morphology and structure of the ER, thereby affecting its function and further disrupting the stable state of cells, leading to the occurrence of disease. In this study, we describe the functions of ER-, ERQC-, and ER-related membrane contact points and their changes under hypoxia, which will help us further understand ER and treat ER-related diseases.
Topics: Endoplasmic Reticulum; Humans; Animals; Endoplasmic Reticulum Stress; Unfolded Protein Response; Hypoxia; Apoptosis; Cell Hypoxia; Endoplasmic Reticulum-Associated Degradation
PubMed: 38781866
DOI: 10.1016/j.biopha.2024.116812 -
Journal of Molecular and Cellular... Jul 2023β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent...
β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent kinase II (CaMKII) and protein kinase D (PKD). Unlike CaMKII, the effects of PKD on excitation-contraction coupling (ECC) remain unclear. To elucidate the mechanisms of PKD-dependent ECC regulation, we used hearts from cardiac-specific PKD1 knockout (PKD1 cKO) mice and wild-type (WT) littermates. We measured calcium transients (CaT), Ca sparks, contraction and L-type Ca current in paced cardiomyocytes under acute β-AR stimulation with isoproterenol (ISO; 100 nM). Sarcoplasmic reticulum (SR) Ca load was assessed by rapid caffeine (10 mM) induced Ca release. Expression and phosphorylation of ECC proteins phospholambam (PLB), troponin I (TnI), ryanodine receptor (RyR), sarcoendoplasmic reticulum Ca ATPase (SERCA) were evaluated by western blotting. At baseline, CaT amplitude and decay tau, Ca spark frequency, SR Ca load, L-type Ca current, contractility, and expression and phosphorylation of ECC protein were all similar in PKD1 cKO vs. WT. However, PKD1 cKO cardiomyocytes presented a diminished ISO response vs. WT with less increase in CaT amplitude, slower [Ca] decline, lower Ca spark rate and lower RyR phosphorylation, but with similar SR Ca load, L-type Ca current, contraction and phosphorylation of PLB and TnI. We infer that the presence of PKD1 allows full cardiomyocyte β-adrenergic responsiveness by allowing optimal enhancement in SR Ca uptake and RyR sensitivity, but not altering L-type Ca current, TnI phosphorylation or contractile response. Further studies are necessary to elucidate the specific mechanisms by which PKD1 is regulating RyR sensitivity. We conclude that the presence of basal PKD1 activity in cardiac ventricular myocytes contributes to normal β-adrenergic responses in Ca handling.
Topics: Animals; Mice; Adrenergic Agents; Adrenergic beta-Agonists; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Mice, Knockout; Myocytes, Cardiac; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Protein Kinase C
PubMed: 37149124
DOI: 10.1016/j.yjmcc.2023.05.001