Current topics in membranes最新文献

Ischemic heart disease is the leading cause of death and a major public health and economic burden worldwide with expectations of predicted growth in the foreseeable future. It is now recognized clinically that flow-limiting stenosis of the large coronary conduit arteries as well as microvascular dysfunction in the absence of severe stenosis can each contribute to the etiology of ischemic heart disease. The primary site of coronary vascular resistance, and control of subsequent coronary blood flow, is found in the coronary microvasculature, where small changes in radius can have profound impacts on myocardial perfusion. Basal active tone and responses to vasodilators and vasoconstrictors are paramount in the regulation of coronary blood flow and adaptations in signaling associated with ion channels are a major factor in determining alterations in vascular resistance and thereby myocardial blood flow. K⁺ channels are of particular importance as contributors to all aspects of the regulation of arteriole resistance and control of perfusion into the myocardium because these channels dictate membrane potential, the resultant activity of voltage-gated calcium channels, and thereby, the contractile state of smooth muscle. Evidence also suggests that K⁺ channels play a significant role in adaptations with cardiovascular disease states. In this review, we highlight our research examining the role of K⁺ channels in ischemic heart disease and adaptations with exercise training as treatment, as well as how our findings have contributed to this area of study.

Cardiovascular disease is on the rise, partially due to the continued increase in metabolic syndrome. Advances in basic research on vascular ion transport have the potential to provide targets for therapeutic interventions. Vascular specificity, which includes different vascular beds having different characteristics and the macro- vs. microvasculature, is a vitally important variable in characterization of ion transport. At the cellular level, targeted fluorescent biosensors for Ca²⁺, super-resolution microscopy, and organelle patch clamp electrophysiology enable more detailed studies. The "MetS/diabetes milieu" includes increased and decreased insulin, and increased glucose, increased LDL/HDL cholesterol and triglycerides, and increased blood pressure. The duration and severity of MetS/diabetes components certainly affect the vascular phenotype and ion transport and membrane interactions. A combination of in vivo animal models and in vitro cell models to study ion transport in MetS/diabetes conditions is optimal. Gene editing and selective pharmacological tools should be used after or in conjunction with characterization of ion transport in vascular health and disease phenotypes. This is critical to determining the causal role of Ca²⁺ signaling in modulation of vascular phenotype. The ion transport and membrane interactions that are measured are typically only a snapshot in time in these dynamic processes occurring over the progression of health and disease. It is imperative that this concept be considered in the planning of long-term studies of vascular disease, ion transport experiments, and interpretation of the data. Future directions for our contributors' research will advance the field.

Transient receptor potential vanilloid 4 (TRPV4) channels are multi-modally activated cation permeable channels that are expressed most organ tissues including the skin. TRPV4 is highly expressed in the skin and functions in skin resident cells such as epidermal keratinocytes, melanocytes, immune mast cells and macrophages, and cutaneous neurons. TRPV4 plays many crucial roles in skin homeostasis to affect an extensive range of processes such as temperature sensation, osmo-sensation, hair growth, cell apoptosis, skin barrier integrity, differentiation, nociception and itch. Since TRPV4 functions in a plenitude of pathological states, TRPV4 can become a versatile therapeutic target for diseases such as chronic pain, itch and skin cancer.

The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and sclera have specialized functions in ocular protection, transparency, accommodation, fluid regulation, metabolism and inflammatory signaling, which are required to enable function of the retina-light sensitive tissue in the posterior eye that transmits visual signals to relay centers in the midbrain. This process can be profoundly impacted by non-visual stimuli such as mechanical (tension, compression, shear), thermal, nociceptive, immune and chemical stimuli, which target these eye regions to induce pain and precipitate vision loss in glaucoma, diabetic retinopathy, retinal dystrophies, retinal detachment, cataract, corneal dysfunction, ocular trauma and dry eye disease. TRPV4, a polymodal nonselective cation channel, integrate non-visual inputs with homeostatic and signaling functions of the eye. The TRPV4 gene is expressed in most if not all ocular tissues, which vary widely with respect to the mechanisms of TRPV4 channel activation, modulation, oligomerization, and participation in protein- and lipid interactions. Under- and overactivation of TRPV4 may affect intraocular pressure, maintenance of blood-retina barriers, lens accommodation, neuronal function and neuroinflammation. Because TRPV4 dysregulation precipitates many pathologies across the anterior and posterior eye, the channel could be targeted to mitigate vision loss.

The delicate balance between constrictor and dilator mechanisms is a vital determinant of blood pressure and blood flow. The maintenance of this balance requires constant communication between different cell-types in the vascular wall. In this regard, the transient receptor potential vanilloid type 4 (TRPV4) ion channel, a Ca²⁺-permeable non-selective cation channel, has emerged as a crucial regulator of Ca²⁺-mediated changes in vascular reactivity. Recent studies suggest that TRPV4 channels regulate vasoconstriction and arterial pressure in the systemic and pulmonary vasculature. New emerging data support a dilatory role of endothelial TRPV4 channels, and both constrictor and dilator roles of smooth muscle TRPV4 channels. Moreover, TRPV4 channel activity has been implicated in physiological functions of vascular support cells, such as fibroblasts and pericytes, to assist the sustenance of vascular reactivity in response to changes in intravascular pressure or external stimulation. Importantly, a growing body of evidence connects abnormal TRPV4 channel activity to multiple vascular disorders. This chapter will review the current literature on the cell-type specific roles of vascular TRPV4 channels in regulating physiological function. Additionally, we summarize our understanding of the contribution of abnormal TRPV4 channel activity to various vascular disorders.

TRPV4 is a non-selective cation channel that belongs to the TRP super family. This channel can be activated by physiological temperatures and mechanical stimuli. In addition, TRPV4 is modulated by several endogenous mediators including specific lipids, cholesterol and their metabolic products. TRPV4 gene is present in all vertebrates and is widely expressed in tissues originating from ectoderm, endoderm and mesoderm. Although TRPV4 knockout is not lethal, point mutations in TRPV4 cause severe clinical phenotypes with variable penetration in human population. These mutations are mostly "gain-of-function" in nature and primarily affect muscles, bones and peripheral neurons, endorsing TRPV4 as critical regulator of musculoskeletal systems. Here we critically analyze the involvement of TRPV4 in musculoskeletal system. Studies of TRPV4 mutations provide detailed information on musculoskeletal disorders at molecular, cellular and metabolic levels.

Langmuir monolayers at gas/liquid interfaces provide a rich framework to investigate the interplay between multiscale geometry and mechanics. Monolayer collapse is investigated at a topological and geometric level by building a scale space M from experimental imaging data. We present a general lipid monolayer collapse phase diagram, which shows that wrinkling, folding, crumpling, shear banding, and vesiculation are a continuous set of mechanical states that can be approached by either tuning monolayer composition or temperature. The origin of the different mechanical states can be understood by investigating the monolayer geometry at two scales: fluorescent vs atomic force microscopy imaging. We show that an interesting switch in continuity occurs in passing between the two scales, C_AFM∈M_AFM≠C_FM∈M. Studying the difference between monolayers that fold vs shear band, we show that shear banding is correlated to the persistence of a multi-length scale microstructure within the monolayer at all surface pressures. A detailed analytical geometric formalism to describe this microstructure is developed using the theory of structured deformations. Lastly, we provide the first ever finite element simulation of lipid monolayer collapse utilizing a direct mapping from the experimental image space M into a simulation domain P. We show that elastic dissipation in the form of bielasticity is a necessary and sufficient condition to capture loss of in-plane stability and shear banding.

Membrane protrusions are a critical facet of cell function. Mediating fundamental processes such as cell migration, cell-cell interactions, phagocytosis, as well as assessment and remodeling of the cell environment. Different protrusion types and morphologies can promote different cellular functions and occur downstream of distinct signaling pathways. As such, techniques to quantify and understand the inner workings of protrusion dynamics are critical for a comprehensive understanding of cell biology. In this chapter, we describe approaches to analyze cellular protrusions and correlate physical changes in cell morphology with biochemical signaling processes. We address methods to quantify and characterize protrusion types and velocity, mathematical approaches to predictive models of cytoskeletal changes, and implementation of protein engineering and biosensor design to dissect cell signaling driving protrusive activity. Combining these approaches allows cell biologists to develop a comprehensive understanding of the dynamics of membrane protrusions.