Mechanical transduction by membrane ion channels: a mini review

There are ion channels in the cell membrane that are sensitive to stress in the membrane cytoskeleton. Some channels turn on with stress, others turn off. In specialized receptors such as those involved in hearing, touch, etc. the role of the channels is clear. However, virtually all cells have these channels, and we don't yet know the physiological role of the channels although it is reasonable to suppose that they are involved in the control of cell size, either acutely as in volume regulation, or trophically as in the control of cell division.     

Energetics of gating MscS by membrane tension in azolectin liposomes and giant spheroplasts

Mechanosensitive (MS) ion channels are molecular sensors that detect and transduce signals across prokaryotic and eukaryotic cell membranes arising from external mechanical stimuli or osmotic gradients. They play an integral role in mechanosensory responses including touch, hearing, and proprioception by opening or closing in order to facilitate or prevent the flow of ions and organic osmolytes. In this study we use a linear force model of MS channel gating to determine the gating membrane tension (γ) and the gating area change (ΔA) associated with the energetics of MscS channel gating in giant spheroplasts and azolectin liposomes. Analysis of Boltzmann distribution functions describing the dependence of MscS channel gating on membrane tension indicated that the gating area change (ΔA) was the same for MscS channels recorded in both preparations. The comparison of the membrane tension (γ) gating the channel, however, showed a significant difference between the MscS channel activities in these two preparations.     

Energetics of gating MscS by membrane tension in azolectin liposomes and giant spheroplasts

Mechanosensitive (MS) ion channels are molecular sensors that detect and transduce signals across prokaryotic and eukaryotic cell membranes arising from external mechanical stimuli or osmotic gradients. They play an integral role in mechanosensory responses including touch, hearing, and proprioception by opening or closing in order to facilitate or prevent the flow of ions and organic osmolytes. In this study we use a linear force model of MS channel gating to determine the gating membrane tension (γ) and the gating area change (ΔA) associated with the energetics of MscS channel gating in giant spheroplasts and azolectin liposomes. Analysis of Boltzmann distribution functions describing the dependence of MscS channel gating on membrane tension indicated that the gating area change (ΔA) was the same for MscS channels recorded in both preparations. The comparison of the membrane tension (γ) gating the channel, however, showed a significant difference between the MscS channel activities in these two preparations.     

Interplay between TRP channels and the cytoskeleton in health and disease

Transient receptor potential (TRP) channels are a family of cation channels that play a key role in ion homeostasis and cell volume regulation. In addition, TRP channels are considered universal integrators of sensory information required for taste, vision, hearing, touch, temperature, and the detection of mechanical force. Seminal investigations exploring the molecular mechanisms of phototransduction in Drosophila have demonstrated that TRP channels operate within macromolecular complexes closely associated with the cytoskeleton. More recent evidence shows that mammalian TRP channels similarly connect to the cytoskeleton to affect cytoskeletal organization and cell adhesion via ion-transport-dependent and -independent mechanisms. In this review, we discuss new insights into the interplay between TRP channels and the cytoskeleton and provide recent examples of such interactions in different physiological systems.     

Drosophila Mechanotransduction—Linking Proteins and Functions

The sensation of touch, gravity, and sound all rely on dedicated ion channels that transduce mechanical stimulus forces into electrical response signals. The functional workings and molecular identities of these mechanotransducer channels are little understood. Recent work shows that the mechanotransducers for fly and vertebrate hearing share equivalent gating mechanisms, whereby this mechanism can be probed non-invasively in the mechanics of the Drosophila ear. Here, we describe how this mechanics can be used to evaluate the roles of identified proteins in the process of mechanosensation and, specifically, their contributions to mechanotransduction.     

Evidence for a protein tether involved in somatic touch

The gating of ion channels by mechanical force underlies the sense of touch and pain. The mode of gating of mechanosensitive ion channels in vertebrate touch receptors is unknown. Here we show that the presence of a protein link is necessary for the gating of mechanosensitive currents in all low‐threshold mechanoreceptors and some nociceptors of the dorsal root ganglia (DRG). Using TEM, we demonstrate that a protein filament with of length ～100 nm is synthesized by sensory neurons and may link mechanosensitive ion channels in sensory neurons to the extracellular matrix. Brief treatment of sensory neurons with non‐specific and site‐specific endopeptidases destroys the protein tether and abolishes mechanosensitive currents in sensory neurons without affecting electrical excitability. Protease‐sensitive tethers are also required for touch‐receptor function in vivo. Thus, unlike the majority of nociceptors, cutaneous mechanoreceptors require a distinct protein tether to transduce mechanical stimuli.     

Drosophila mechanotransduction--linking proteins and functions

The sensation of touch, gravity, and sound all rely on dedicated ion channels that transduce mechanical stimulus forces into electrical signals. The functional workings and molecular identities of these mechanotransducer channels are little understood. Recent work shows that the mechanotransducers for fly and vertebrate hearing share equivalent gating mechanisms, whereby this mechanism can be probed non-invasively in the mechanics of the Drosophila ear. Here, we describe how this mechanics can be used to evaluate the roles of identified proteins in the process of mechanosensation and, specifically, their contributions to mechanotransduction.     

A genetic basis for mechanosensory traits in humans

In all vertebrates hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. There is an extensive literature describing single gene mutations in humans that cause hearing impairment, but there are essentially none for touch. Here we first asked if touch sensitivity is a heritable trait and second whether there are common genes that influence different mechanosensory senses like hearing and touch in humans. Using a classical twin study design we demonstrate that touch sensitivity and touch acuity are highly heritable traits. Quantitative phenotypic measures of different mechanosensory systems revealed significant correlations between touch and hearing acuity in a healthy human population. Thus mutations in genes causing deafness genes could conceivably negatively influence touch sensitivity. In agreement with this hypothesis we found that a proportion of a cohort of congenitally deaf young adults display significantly impaired measures of touch sensitivity compared to controls. In contrast, blind individuals showed enhanced, not diminished touch acuity. Finally, by examining a cohort of patients with Usher syndrome, a genetically well-characterized deaf-blindness syndrome, we could show that recessive pathogenic mutations in the USH2A gene influence touch acuity. Control Usher syndrome cohorts lacking demonstrable pathogenic USH2A mutations showed no impairment in touch acuity. Our study thus provides comprehensive evidence that there are common genetic elements that contribute to touch and hearing and has identified one of these genes as USH2A.     

Zebrafish heart as a model for human cardiac electrophysiology

The zebrafish (Danio rerio) has become a popular model for human cardiac diseases and pharmacology including cardiac arrhythmias and its electrophysiological basis. Notably, the phenotype of zebrafish cardiac action potential is similar to the human cardiac action potential in that both have a long plateau phase. Also the major inward and outward current systems are qualitatively similar in zebrafish and human hearts. However, there are also significant differences in ionic current composition between human and zebrafish hearts, and the molecular basis and pharmacological properties of human and zebrafish cardiac ionic currents differ in several ways. Cardiac ionic currents may be produced by non-orthologous genes in zebrafish and humans, and paralogous gene products of some ion channels are expressed in the zebrafish heart. More research on molecular basis of cardiac ion channels, and regulation and drug sensitivity of the cardiac ionic currents are needed to enable rational use of the zebrafish heart as an electrophysiological model for the human heart.     

Neurosensory mechanotransduction through acid‐sensing ion channels

Acid‐sensing ion channels (ASICs) are voltage‐insensitive cation channels responding to extracellular acidification. ASIC proteins have two transmembrane domains and a large extracellular domain. The molecular topology of ASICs is similar to that of the mechanosensory abnormality 4‐ or 10‐proteins expressed in touch receptor neurons and involved in neurosensory mechanotransduction in nematodes. The ASIC proteins are involved in neurosensory mechanotransduction in mammals. The ASIC isoforms are expressed in Merkel cell–neurite complexes, periodontal Ruffini endings and specialized nerve terminals of skin and muscle spindles, so they might participate in mechanosensation. In knockout mouse models, lacking an ASIC isoform produces defects in neurosensory mechanotransduction of tissue such as skin, stomach, colon, aortic arch, venoatrial junction and cochlea. The ASICs are thus implicated in touch, pain, digestive function, baroreception, blood volume control and hearing. However, the role of ASICs in mechanotransduction is still controversial, because we lack evidence that the channels are mechanically sensitive when expressed in heterologous cells. Thus, ASIC channels alone are not sufficient to reconstruct the path of transducing molecules of mechanically activated channels. The mechanotransducers associated with ASICs need further elucidation. In this review, we discuss the expression of ASICs in sensory afferents of mechanoreceptors, findings of knockout studies, technical issues concerning studies of neurosensory mechanotransduction and possible missing links. Also we propose a molecular model and a new approach to disclose the molecular mechanism underlying the neurosensory mechanotransduction.     

Mechanotransduction by TRP Channels: General Concepts and Specific Role in the Vasculature

Transient receptor potential (TRP) ion channel superfamily is involved in sensing and transmission of a broad variety of external or internal stimuli, including but not limited to mechanical stress. Based on homology analysis, genetic and molecular studies have recently identified TRP channels in different tissues, comprising blood vessels. In invertebrates, many TRP channels including five TRPV channels identified in Caenorhabditis elegans and two in Drosophila have been implicated in mechanosensory behaviors as molecular basis of volume regulation, hearing and touch sensitivity. Consistently, in mammals many TRP family members such as TRPC1, TRPC3, TRPC6, TRPM4, TRPM7, TRPN1, TRPA1, TRPY1, TRPP1, TRPP2, and notably, TRPV1, TPRV2 as well as TRPV4 have been reported to be involved in mechanotransduction. This review summarizes recent and at times controversial findings on the role and regulation of TRP channels in mechanotransduction. Specifically, we highlight the relevance of TRPV channels in vascular regulation and focus on TRPV4 in the vascular system of the lung, which is constantly exposed to a unique combination of circumferential and longitudinal strains. In light of our observation in intact pulmonary microvessels that mechanical stress induced Ca²⁺ signaling in endothelial cells is closely related to TRPV4 activity, we postulate that TRPV4 plays a critical role in lung vascular mechanotransduction. The progress in this rapidly expanding field may allow for the identification of new molecular targets and the development of new therapeutic approaches in a number of intractable diseases related to mechanical stress.     

Vertebrate and invertebrate TRPV-like mechanoreceptors

Our senses of touch, hearing, and balance are mediated by mechanosensitive ion channels. In vertebrates, little is known about the molecular composition of these mechanoreceptors, an example of which is the transduction channel of the inner ear's receptor cells, hair cells. Members of the TRP family of ion channels are considered candidates for the vertebrate hair cell's mechanosensitive transduction channel and here we review the evidence for this candidacy. We start by examining the results of genetic screens in invertebrates that identified members of the TRP gene family as core components of mechanoreceptors. In particular, we discuss the Caenorhabditis elegans OSM-9 channel, an invertebrate TRPV channel, and the Drosophila melanogaster TRP channel NOMPC. We then evaluate basic features of TRPV4, a vertebrate member of the TRPV subfamily, which is gated by a variety of physical and chemical stimuli including temperature, osmotic pressure, and ligands. Finally, we compare the characteristics of all discussed mechanoreceptive TRP channels with the biophysical characteristics of hair cell mechanotransduction, speculating about the possible make-up of the elusive inner ear mechanoreceptor.     

Mechanosensitive channels: in touch with Piezo

Mechanosensory transduction underlies touch, hearing and proprioception and requires mechanosensitive channels that are directly gated by forces; however, the molecular identities of these channels remain largely elusive. A new study has identified Piezo1 and Piezo2 as a novel class of mechanosensitive channels.     

多不饱和脂肪酸对钾通道的调控作用及机理

多不饱和脂肪酸具有包括离子通道在内的众多作用靶点,通过作用于这些靶点,可以有效保护免疫系统、神经系统和心血管系统的功能,在一定程度上保护人体健康。电压门控钾离子通道家族K_V7通道和大电导钙离子激活的钾离子通道(BK_Ca)广泛表达于机体的各类组织中,具有重要的生理或病理功能。本综述围绕K_V7和BK_Ca通道,根据对已有报道的汇总,多不饱和脂肪酸可以增大K_V7和BK_Ca通道的电流幅值,其中对K_V7通道电流的影响主要是改变其电压依赖特性和最大电导值,而对BK_Ca通道电流的影响主要是改变其孔道区域关闭态的构象。此外,多不饱和脂肪酸对K_V7和BK_Ca通道功能的调节也会受到共表达的辅助亚基影响,但相关机制有待进一步阐明。深入理解多不饱和脂肪酸对K_V7和BK_Ca通道调节作用效果和分子机制,有助于全面理解K_V7和BK     

电压门控钠离子通道疾病的研究进展

细胞膜上的电压门控钠离子通道（Voltage-gated Sodium Channels,VGSCs）是细胞形成动作电位过程中重要的组成构件,由一个大的α亚基和一个或多个不同的β亚基组成,中央是具高度选择性只允许钠离子通过的亲水通道。电压门控钠离子通道在调节细胞膜电位、维持细胞离子稳态、细胞增殖和凋亡等生理过程中发挥着重要作用,因而钠离子通道自身的异变或是相关基因的变异都可能引起一系列身体病变。本文主要介绍了电压门控钠离子通道的结构与功能,阐述了其与癌细胞侵袭转移和神经病理性疼痛的关系,并介绍了几种典型的由钠离子通道基因变异引起的疾病。随着对电压门控钠离子通道及其异常分子机制研究的不断深入,新成果将为生理学、药理学和病理学等领域的研究提供理论基础和新的研究思路,为离子通道疾病的临床预防、诊断与治疗找到新途径。     

昆虫分子生物学的一些进展：神经递质和离子通道

昆虫分子生物学的一些进展：神经递质和离子通道翟启慧（中国科学院动物研究所北京１０００８０）１神经递质神经递质（ｎｅｕｒｏｔｒａｎ。ｍｉｔｔｅｒ）是在化学突触神经ｆＧ。１问传递信息的化学物质。神经递质有许多不同类型,如乙酸胆碱、丫一氨基丁酸、生物胺等。...     

Anesthetic-mediated protection/preconditioning during cerebral ischemia

Cerebral ischemia is a multi-faceted neurodegenerative pathology that causes cellular injury to neurons within the central nervous system. In light of the underlying mechanisms being elucidated, clinical trials to find possible neuroprotectants to date have failed, thus highlighting the need for new putative targets to offer protection. Recent evidence has clearly shown that anesthetics can confer significant protection and or induce a preconditioning effect against cerebral ischemia-induced injury. This review will focus on the putative protection/preconditioning that is afforded by anesthetics, their possible interaction with GABA(A) and glutamate receptors and two-pore potassium channels. In addition, the interaction with inflammatory, apoptotic and underlying molecular (particularly immediately early genes and inducible nitric oxide synthase etc) pathways, the activation of K(ATP) channels and the ability to provide lasting protection will also be addressed.     

TRP channels in mechanosensation: direct or indirect activation?

Ion channels of the transient receptor potential (TRP) superfamily are involved in a wide variety of neural signalling processes, most prominently in sensory receptor cells. They are essential for mechanosensation in systems ranging from fruitfly hearing, to nematode touch, to mouse mechanical pain. However, it is unclear in many instances whether a TRP channel directly transduces the mechanical stimulus or is part of a downstream signalling pathway. Here, we propose criteria for establishing direct mechanical activation of ion channels and review these criteria in a number of mechanosensory systems in which TRP channels are involved.     

酸敏感离子通道的功能及其相关调控

酸敏感离子通道（ASICs）是一类由胞外酸化所激活的阳离子通道.目前,已发现了6个ASICs亚基,它们在外周和中枢神经系统中广泛表达.利用基因敲除等技术,已证明它们在触觉、痛觉、酸味觉以及学习记忆中具有重要作用.同时,它们也参与某些病理反应.ASICs可以被神经肽、温度、金属离子和缺血相关物质等调控,从而整合细胞周围的多种信号以行使其功能.