Current topics in membranes最新文献

The cytoplasmic Ca²⁺ concentration and the activity of K⁺ channels on the plasma membrane regulate cellular processes ranging from mitosis to oriented migration. The interplay between Ca²⁺ and K⁺ signals is intricate, and different cell types rely on peculiar cellular mechanisms. Derangement of these mechanisms accompanies the neoplastic progression. The calcium signals modulated by voltage-gated (K_V) and calcium-dependent (K_Ca) K⁺ channel activity regulate progression of the cell division cycle, the release of growth factors, apoptosis, cell motility and migration. Moreover, K_V channels regulate the cell response to the local microenvironment by assembling with cell adhesion and growth factor receptors. This chapter summarizes the pathophysiological roles of Ca²⁺ and K⁺ fluxes in normal and cancer cells, by concentrating on several biological systems in which these functions have been studied in depth, such as early embryos, mammalian cell lines, T lymphocytes, gliomas and colorectal cancer cells. A full understanding of the underlying mechanisms will offer a comprehensive view of the ion channel implication in cancer biology and suggest potential pharmacological targets for novel therapeutic approaches in oncology.

All cells in the human body are covered by a complex meshwork of sugars as well as proteins and lipids to which these sugars are attached, collectively termed the glycocalyx. Over the past few decades, the glycocalyx has been implicated in a range of vital cellular processes in health and disease. Therefore, it has attracted considerable interest as a therapeutic target. Considering its omnipresence and its relevance for various areas of cell biology, the glycocalyx should be a versatile platform for therapeutic intervention, however, the full potential of the glycocalyx as therapeutic target is yet to unfold. This might be attributable to the fact that glycocalyx alterations are currently discussed mainly in the context of specific diseases. In this perspective review, we shift the attention away from a disease-centered view of the glycocalyx, focusing on changes in glycocalyx state. Furthermore, we survey important glycocalyx-targeted drugs currently available and finally discuss future steps. We hope that this approach will inspire a unified, holistic view of the glycocalyx in disease, helping to stimulate novel glycocalyx-targeted therapy strategies.

Voltage-gated sodium channels (Na_v) are protein complexes that play fundamental roles in the transmission of signals in the nervous system, at the neuromuscular junction and in the heart. They are mainly present in excitable cells where they are responsible for triggering action potentials. Dysfunctions in Na_v ion conduction give rise to a wide range of conditions, including neurological disorders, hypertension, arrhythmia, pain and cancer. Na_v family 1 is composed of nine members, named numerically from 1 to 9. A Nax family also exists and is involved in body-fluid homeostasis. Of particular interest is Na_v1.7 which is highly expressed in the sensory neurons of the dorsal root ganglions, where it is involved in the propagation of pain sensation. Gain-of-function mutations in Na_v1.7 cause pathologies associated with increased pain sensitivity, while loss-of-function mutations cause reduced sensitivity to pain. The last decade has seen considerable effort in developing highly specific Na_v1.7 blockers as pain medications, nonetheless, sufficient efficacy has yet to be achieved. Evidence is now conclusively showing that Na_vs are also present in many types of cancer cells, where they are involved in cell migration and invasiveness. Na_v1.7 is anomalously expressed in endometrial, ovarian and lung cancers. Na_v1.7 is also involved in Chemotherapy Induced Peripheral Neuropathy (CIPN). We propose that the knowledge and tools developed to study the role of Na_v1.7 in pain can be exploited to develop novel cancer therapies. In this chapter, we illustrate the various aspects of Na_v1.7 function in pain, cancer and CIPN, and outline therapeutic approaches.

Kidneys are central for whole body water and electrolyte balance by first filtering plasma at the glomeruli and then processing the filtrate along the renal nephron until the final urine is produced. Renal nephron epithelial cells mediate transport of water and solutes which is under the control of systemic hormones as well as local mechanical stimuli arising from alterations in fluid flow. TRPV4 is a mechanosensitive Ca²⁺ channel abundantly expressed in different segments of the renal nephron. The accumulated evidence suggests a critical role for TRPV4 in sensing variations in flow rates. In turn, TRPV4 activation triggers numerous downstream cellular responses stimulated by elevated intracellular Ca²⁺ concentrations [Ca²⁺]_i. In this review, we discuss the recent concepts in flow-mediated regulation of solute homeostasis by TRPV4 in different segments of renal nephron. Specifically, we summarize the evidence for TRPV4 involvement in endocytosis-mediated albumin uptake in the proximal tubule, reactive oxygen species (ROS) generation in the ascending loop of Henle, and maintaining K⁺ homeostasis in the connecting tubule/collecting duct. Finally, we outline the function and significance of TRPV4 in the setting of polycystic kidney disease.

Transient receptor potential vanilloid sub-type 4 (TRPV4) is a six transmembrane protein that acts as a non-selective Ca²⁺ channel. Notably, TRPV4 is present in almost all animals, from lower eukaryotes to humans and is expressed in diverse tissue and cell types. Accordingly, TRPV4 is endogenously expressed in several types of immune cells that represent both innate and adaptive immune systems of higher organism. TRPV4 is known to be activated by physiological temperature, suggesting that it acts as a molecular temperature sensor and thus plays a key role in temperature-dependent immune activation. It is also activated by diverse endogenous ligands, lipid metabolites, physical and mechanical stimuli. Both expression and function of TRPV4 in various immune cells, including T cells and macrophages, are also modulated by multiple pro- and anti-inflammatory compounds. The results from several laboratories suggest that TRPV4 is involved in the immune activation, a phenomenon with evolutionary significance. Because of its diverse engagement in the neuronal and immune systems, TRPV4 is a potential therapeutic target for several immune-related disorders.

Vascular smooth muscle cells express several isoforms of a number of classes of K⁺ channels. Potassium channels play critical roles in the regulation of vascular smooth muscle contraction as well as vascular smooth muscle cell proliferation or phenotypic modulation. There is ample evidence that it is Ca²⁺ that enables these two seemingly disparate functions to be tightly coupled both in healthy and disease processes. Because of the central position that potassium channels have in vasocontraction, vasorelaxation, membrane potential, and smooth muscle cell proliferation, these channels continue to possess the potential to serve as novel therapeutic targets in cardiovascular disease. While there are questions that remain regarding the complete interactions between K⁺ channels, vascular regulation, smooth muscle cell proliferation, and phenotypic modulation in physiological and pathophysiological conditions, a broad understanding of the contributions of each class of K⁺ channel to contractile and proliferative states of the vasculature has been reached. This brief review will discuss the current understanding of the role of K⁺ channels in vascular smooth muscle cells in health and disease using the porcine vascular smooth muscle cell model with particular attention to new scientific discoveries contributed by the authors regarding the effect of endurance exercise on the function of the K⁺ channels.

Ischemic heart disease due to macrovascular atherosclerosis and microvascular dysfunction is the major cause of death worldwide and the unabated increase in metabolic syndrome is a major reason why this will continue. Intracellular free Ca²⁺ ([Ca²⁺]_i) regulates a variety of cellular functions including contraction, proliferation, migration, and transcription. It follows that studies of vascular Ca²⁺ regulation in reductionist models and translational animal models are vital to understanding vascular health and disease. Swine with metabolic syndrome (MetS) develop the full range of coronary atherosclerosis from mild to severe disease. Intravascular imaging enables quantitative measurement of atherosclerosis in vivo, so viable coronary smooth muscle (CSM) cells can be dispersed from the arteries to enable Ca²⁺ transport studies in native cells. Transition of CSM from the contractile phenotype in the healthy swine to the proliferative phenotype in mild atherosclerosis was associated with increases in SERCA activity, sarcoplasmic reticulum Ca²⁺, and voltage-gated Ca²⁺ channel function. In vitro organ culture confirmed that SERCA activation induces CSM proliferation. Transition from the proliferative to a more osteogenic phenotype was associated with decreases in all three Ca²⁺ transporters. Overall, there was a biphasic change in Ca²⁺ transporters over the progression of atherosclerosis in the swine model and this was confirmed in CSM from failing explanted hearts of humans. A major determinant of endolysosome content in human CSM is the severity of atherosclerosis. In swine CSM endolysosome Ca²⁺ release occurred through the TPC2 channel. We propose a multiphasic change in Ca²⁺ transporters over the progression of coronary atherosclerosis.

Transient Receptor Potential Vanilloid 4 (TRPV4) is expressed in numerous cell types within the heart, yet the expression levels, subcellular localization, and functional relevance of TRPV4 in cardiac myocytes is under-appreciated. Recent data indicate a critical role of TRPV4 in both atrial and ventricular myocyte biology, with expression levels and channel function increasing following pathological scenarios including ischemia, myocardial infarction, mechanical stress, and inflammation. Excessive activation of TRPV4 at the cellular level contributes to enhanced Ca²⁺ entry which predisposes the cardiac myocyte to pro-arrhythmic Ca²⁺ overload and electrophysiological abnormalities. At the organ level, excessive TRPV4 activity associates with cardiac hypercontractility, cardiac damage, ventricular arrhythmia, and atrial fibrillation. This manuscript chapter describes the emerging literature on TRPV4 in cardiac myocytes in physiology and disease.

Lysosomal acid ceramidase (AC) has been reported to determine multivesicular body (MVB) fate and exosome secretion in different mammalian cells including coronary arterial endothelial cells (CAECs). However, this AC-mediated regulation of exosome release from CAECs and associated underlying mechanism remain poorly understood. In the present study, we hypothesized that AC controls lysosomal Ca²⁺ release through TRPML1 channel to regulate exosome release in murine CAECs. To test this hypothesis, we isolated and cultured CAECs from WT/WT and endothelial cell-specific Asah1 gene (gene encoding AC) knockout mice. Using these CAECs, we first demonstrated a remarkable increase in exosome secretion and significant reduction of lysosome-MVB interaction in CAECs lacking Asah1 gene compared to those cells from WT/WT mice. ML-SA1, a TRPML1 channel agonist, was found to enhance lysosome trafficking and increase lysosome-MVB interaction in WT/WT CAECs, but not in CAECs lacking Asah1 gene. However, sphingosine, an AC-derived sphingolipid, was able to increase lysosome movement and lysosome-MVB interaction in CAECs lacking Asah1 gene, leading to reduced exosome release from these cells. Moreover, Asah1 gene deletion was shown to substantially inhibit lysosomal Ca²⁺ release through suppression of TRPML1 channel activity in CAECs. Sphingosine as an AC product rescued the function of TRPML1 channel in CAECs lacking Asah1 gene. These results suggest that Asah1 gene defect and associated deficiency of AC activity may inhibit TRPML1 channel activity, thereby reducing MVB degradation by lysosome and increasing exosome release from CAECs. This enhanced exosome release from CAECs may contribute to the development of coronary arterial disease under pathological conditions.