Showing papers in "Physiological Reviews in 2006"
TL;DR: The molecular and biochemical characterization of HOs is reviewed, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress, to lay a foundation for potential future clinical applications of these systems.
Abstract: The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.
2,111 citations
TL;DR: Based on the current knowledge of the role of cytokines in atherosclerosis, some novel therapeutic strategies to combat this disease are proposed and the potential of circulating cytokine levels as biomarkers of coronary artery disease is discussed.
Abstract: Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.
1,587 citations
TL;DR: This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.
Abstract: The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite "sensor" that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. Interendothelial junctions comprise a complex array of proteins in series with the extracellular matrix constituents and serve to limit the transport of albumin and other plasma proteins by the paracellular pathway. This pathway is highly regulated by the activation of specific extrinsic and intrinsic signaling pathways. Recent evidence has also highlighted the importance of the heretofore enigmatic transcellular pathway in mediating albumin transport via transcytosis. Caveolae, the vesicular carriers filled with receptor-bound and unbound free solutes, have been shown to shuttle between the vascular and extravascular spaces depositing their contents outside the cell. This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.
1,575 citations
TL;DR: A large body of data is now available to support the existence of numerous organ-based RAS exerting diverse physiological effects, and universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli.
Abstract: Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.
1,543 citations
TL;DR: The application of subcellular imaging of Ca2+ signaling to astrocytes now provides functional data to support this structural notion that both excitatory and inhibitory signals provided by the same glial cell act in concert to regulate neuronal function.
Abstract: From a structural perspective, the predominant glial cell of the central nervous system, the astrocyte, is positioned to regulate synaptic transmission and neurovascular coupling: the processes of ...
1,251 citations
TL;DR: This review discusses the structural and functional bases that generate the subcellular heterogeneity in cellular Ca(2+) levels at rest and under stimulation, and focuses on the molecular mechanisms that lead to the generation of cytoplasmic Ca( 2+) microdomains, focusing on their different sub cellular location, mechanism of generation, and functional role.
Abstract: Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different int...
1,104 citations
TL;DR: Understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes, and deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease.
Abstract: This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein ba...
1,004 citations
TL;DR: Together these mechanisms contribute to the continuous dynamic adjustment of sensorimotor interactions, ensuring that the central program and feedback mechanisms are congruous during locomotion.
Abstract: Locomotion results from intricate dynamic interactions between a central program and feedback mechanisms. The central program relies fundamentally on a genetically determined spinal circuitry (central pattern generator) capable of generating the basic locomotor pattern and on various descending pathways that can trigger, stop, and steer locomotion. The feedback originates from muscles and skin afferents as well as from special senses (vision, audition, vestibular) and dynamically adapts the locomotor pattern to the requirements of the environment. The dynamic interactions are ensured by modulating transmission in locomotor pathways in a state- and phase-dependent manner. For instance, proprioceptive inputs from extensors can, during stance, adjust the timing and amplitude of muscle activities of the limbs to the speed of locomotion but be silenced during the opposite phase of the cycle. Similarly, skin afferents participate predominantly in the correction of limb and foot placement during stance on uneven terrain, but skin stimuli can evoke different types of responses depending on when they occur within the step cycle. Similarly, stimulation of descending pathways may affect the locomotor pattern in only certain phases of the step cycle. Section ii reviews dynamic sensorimotor interactions mainly through spinal pathways. Section iii describes how similar sensory inputs from the spinal or supraspinal levels can modify locomotion through descending pathways. The sensorimotor interactions occur obviously at several levels of the nervous system. Section iv summarizes presynaptic, interneuronal, and motoneuronal mechanisms that are common at these various levels. Together these mechanisms contribute to the continuous dynamic adjustment of sensorimotor interactions, ensuring that the central program and feedback mechanisms are congruous during locomotion.
1,003 citations
TL;DR: This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.
Abstract: The extracellular space is an environment hostile to unmodified polypeptides. For this reason, many eukaryotic proteins destined for exposure to this environment through secretion or display at the cell surface require maturation steps within a specialized organelle, the endoplasmic reticulum (ER). A complex homeostatic mechanism, known as the unfolded protein response (UPR), has evolved to link the load of newly synthesized proteins with the capacity of the ER to mature them. It has become apparent that dysfunction of the UPR plays an important role in some human diseases, especially those involving tissues dedicated to extracellular protein synthesis. Diabetes mellitus is an example of such a disease, since the demands for constantly varying levels of insulin synthesis make pancreatic β-cells dependent on efficient UPR signaling. Furthermore, recent discoveries in this field indicate that the importance of the UPR in diabetes is not restricted to the β-cell but is also involved in peripheral insulin resistance. This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.
892 citations
TL;DR: This review reviews data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism and discusses how transcription factors integrate signals from various pathways to ensure homeostasis.
Abstract: Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the ...
840 citations
TL;DR: What is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates are described and evidence that they may be involved in the clinical drug resistance of various forms of cancer is summarized.
Abstract: Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the ...
TL;DR: It is suggested that multidrug transporters are essential parts of an innate defense system, the "chemoimmunity" network, which has a number of features reminiscent of classical immunology.
Abstract: In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistanc...
TL;DR: The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress and hormones, and may play an active role in a multitude of pathophysiological conditions.
Abstract: The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocort...
TL;DR: Spike timing-dependent modification of neuronal excitability and dendritic integration was observed and such STDP at the synaptic and cellular level is likely to play important roles in activity-induced functional changes in neuronal receptive fields and human perception.
Abstract: Information in the nervous system may be carried by both the rate and timing of neuronal spikes. Recent findings of spike timing-dependent plasticity (STDP) have fueled the interest in the potential roles of spike timing in processing and storage of information in neural circuits. Induction of long-term potentiation (LTP) and long-term depression (LTD) in a variety of in vitro and in vivo systems has been shown to depend on the temporal order of pre- and postsynaptic spiking. Spike timing-dependent modification of neuronal excitability and dendritic integration was also observed. Such STDP at the synaptic and cellular level is likely to play important roles in activity-induced functional changes in neuronal receptive fields and human perception.
TL;DR: The mechanisms used by homeothermic species to generate more heat and their regulation largely by thyroid hormone and the sympathetic nervous system are reviewed, finding that thyroid hormone plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulated the responses to SNS.
Abstract: Increased heat generation from biological processes is inherent to homeothermy. Homeothermic species produce more heat from sustaining a more active metabolism as well as from reducing fuel efficie...
TL;DR: It is concluded that lamins seem to be key players in, among others, controlling the process of cellular ageing, since disturbance in lamin protein structure gives rise to several forms of premature ageing.
Abstract: It has been demonstrated that nuclear lamins are important proteins in maintaining cellular as well as nuclear integrity, and in maintaining chromatin organization in the nucleus. Moreover, there is growing evidence that lamins play a prominent role in transcriptional control. The family of laminopathies is a fast-growing group of diseases caused by abnormalities in the structure or processing of the lamin A/C (LMNA) gene. Mutations or incorrect processing cause more than a dozen different inherited diseases, ranging from striated muscular diseases, via fat- and peripheral nerve cell diseases, to progeria. This broad spectrum of diseases can only be explained if the responsible A-type lamin proteins perform multiple functions in normal cells. This review gives an overview of current knowledge on lamin structure and function and all known diseases associated with LMNA abnormalities. Based on the knowledge of the different functions of A-type lamins and associated proteins, explanations for the observed phenotypes are postulated. It is concluded that lamins seem to be key players in, among others, controlling the process of cellular ageing, since disturbance in lamin protein structure gives rise to several forms of premature ageing.
TL;DR: Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin.
Abstract: This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.
TL;DR: The role of lipids in development of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed, and the influence of diet, training, and gender is discussed.
Abstract: Lipids as fuel for energy provision originate from different sources: albumin-bound long-chain fatty acids (LCFA) in the blood plasma, circulating very-low-density lipoproteins-triacylglycerols (VLDL-TG), fatty acids from triacylglycerol located in the muscle cell (IMTG), and possibly fatty acids liberated from adipose tissue adhering to the muscle cells. The regulation of utilization of the different lipid sources in skeletal muscle during exercise is reviewed, and the influence of diet, training, and gender is discussed. Major points deliberated are the methods utilized to measure uptake and oxidation of LCFA during exercise in humans. The role of the various lipid-binding proteins in transmembrane and cytosolic transport of lipids is considered as well as regulation of lipid entry into the mitochondria, focusing on the putative role of AMP-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), and carnitine during exercise. The possible contribution to fuel provision during exercise of circulating VLDL-TG as well as the role of IMTG is discussed from a methodological point of view. The contribution of IMTG for energy provision may not be large, covering ∼10% of total energy provision during fasting exercise in male subjects, whereas in females, IMTG may cover a larger proportion of energy delivery. Molecular mechanisms involved in breakdown of IMTG during exercise are also considered focusing on hormone-sensitive lipase (HSL). Finally, the role of lipids in development of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed.
TL;DR: It is concluded on balance that the evidence points to a need for phosphoinositide/calcium signaling during resumption of meiosis, and it is concluded that calcium signals are essential at all three stages of cell division in early embryos.
Abstract: Fertilization calcium waves are introduced, and the evidence from which we can infer general mechanisms of these waves is presented. The two main classes of hypotheses put forward to explain the ge...
TL;DR: General properties of the receptors are described, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation are described.
Abstract: Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.
TL;DR: Differential effects of adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including theMedullary thick ascending limb.
Abstract: In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.
TL;DR: Data show that cGKs are signaling molecules involved in many biological functions, and in vivo targets and mechanisms leading to changes in neuronal adaptation, smooth muscle relaxation and growth, intestinal water secretion, bone growth, renin secretion, and other important functions have been identified.
Abstract: Over the past few years, a wealth of biochemical and functional data have been gathered on mammalian cGMP-dependent protein kinases (cGKs). In mammals, three different kinases are encoded by two genes. Mutant and chimeric cGK proteins generated by molecular biology techniques yielded important biochemical knowledge, such as the function of the NH2-terminal domains of cGKI and cGKII, the identity of the cGMP-binding sites of cGKI, and the substrate specificity of the enzymes. Genetic approaches have proven especially useful for the analysis of the biological functions of cGKs. Recently, some of the in vivo targets and mechanisms leading to changes in neuronal adaptation, smooth muscle relaxation and growth, intestinal water secretion, bone growth, renin secretion, and other important functions have been identified. These data show that cGKs are signaling molecules involved in many biological functions.
TL;DR: This review summarizes the emerging view of the spatial organization of the odorant receptor maps and suggests that the glomerular sheet represents the characteristic molecular features in a systematic, gradual, and multidimensional fashion.
Abstract: The olfactory bulb (OB) is the first relay station of the central olfactory system in the mammalian brain and contains a few thousand glomeruli on its surface. Because individual glomeruli represen...
TL;DR: It is proposed that chromaffin cells have developed functional triads that are formed by calcium channels, the ER, and the mitochondria and locally control the [Ca2+]c that regulate the early and late steps of exocytosis.
Abstract: At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca2+ concentration ([Ca2+]c) depends on at least four efficient regulatory systems: 1) plasmalemmal calcium channels,...
TL;DR: Practical interventions for prevention of weight and fat fluctuations in old age are anticipated here based on emerging knowledge of the role of such factors as dietary variety, taste, and palatability in late-life energy regulation.
Abstract: Changes in energy regulation occur during normal aging and contribute to the common phenomenon of weight and fat losses late in life. This review synthesizes data on aging-related changes in energy intake and energy expenditure and on the regulation of energy intake and expenditure. The ability of older adults to accurately regulate energy intake is impaired, with a number of possible explanations including delayed rate of absorption of macronutrients secondary to reductions in taste and smell acuity and numerous hormonal and metabolic mediators of energy regulation that change with aging. There are also changes in patterns of dietary intake and a reduction in the variety of foods consumed in old age that are thought to further reduce energy intake. Additionally, all components of energy expenditure decrease with aging, in particular energy expenditure for physical activity and basal metabolic rate, and the ability of energy expenditure to increase or decrease to attenuate energy imbalance during overeating or undereating also decreases. Combined, these changes result in an increased susceptibility to energy imbalance (both positive and negative) in old age that is associated with deteriorations in health. Practical interventions for prevention of weight and fat fluctuations in old age are anticipated here based on emerging knowledge of the role of such factors as dietary variety, taste, and palatability in late-life energy regulation.
TL;DR: From this analysis, M+ complexation has the potential to be an efficient regulator of enzyme catalysis and stability and offers novel strategies for protein engineering to improve enzyme function.
Abstract: Metal complexation is a key mediator or modifier of enzyme structure and function. In addition to divalent and polyvalent metals, group IA metals Na+ and K+ play important and specific roles that assist function of biological macromolecules. We examine the diversity of monovalent cation (M+)-activated enzymes by first comparing coordination in small molecules followed by a discussion of theoretical and practical aspects. Select examples of enzymes that utilize M+ as a cofactor (type I) or allosteric effector (type II) illustrate the structural basis of activation by Na+ and K+, along with unexpected connections with ion transporters. Kinetic expressions are derived for the analysis of type I and type II activation. In conclusion, we address evolutionary implications of Na+ binding in the trypsin-like proteases of vertebrate blood coagulation. From this analysis, M+ complexation has the potential to be an efficient regulator of enzyme catalysis and stability and offers novel strategies for protein engineering to improve enzyme function.
TL;DR: The cardiac muscle and the coronary vasculature are in close proximity to each other, and a two-way interaction, called cross-talk, exists, and here the authors focus on the mechanical aspects of cross- talk including the role of the extracellular matrix.
Abstract: The cardiac muscle and the coronary vasculature are in close proximity to each other, and a two-way interaction, called cross-talk, exists. Here we focus on the mechanical aspects of cross-talk including the role of the extracellular matrix. Cardiac muscle affects the coronary vasculature. In diastole, the effect of the cardiac muscle on the coronary vasculature depends on the (changes in) muscle length but appears to be small. In systole, coronary artery inflow is impeded, or even reversed, and venous outflow is augmented. These systolic effects are explained by two mechanisms. The waterfall model and the intramyocardial pump model are based on an intramyocardial pressure, assumed to be proportional to ventricular pressure. They explain the global effects of contraction on coronary flow and the effects of contraction in the layers of the heart wall. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model are based on direct contact between muscles and vessels. They predict global effects as well as differences on flow in layers and flow heterogeneity due to contraction. The relative contributions of these two mechanisms depend on the wall layer (epi- or endocardial) and type of contraction (isovolumic or shortening). Intramyocardial pressure results from (local) muscle contraction and to what extent the interstitial cavity contracts isovolumically. This explains why small arterioles and venules do not collapse in systole. Coronary vasculature affects the cardiac muscle. In diastole, at physiological ventricular volumes, an increase in coronary perfusion pressure increases ventricular stiffness, but the effect is small. In systole, there are two mechanisms by which coronary perfusion affects cardiac contractility. Increased perfusion pressure increases microvascular volume, thereby opening stretch-activated ion channels, resulting in an increased intracellular Ca2+ transient, which is followed by an increase in Ca2+ sensitivity and higher muscle contractility (Gregg effect). Thickening of the shortening cardiac muscle takes place at the expense of the vascular volume, which causes build-up of intracellular pressure. The intracellular pressure counteracts the tension generated by the contractile apparatus, leading to lower net force. Therefore, cardiac muscle contraction is augmented when vascular emptying is facilitated. During autoregulation, the microvasculature is protected against volume changes, and the Gregg effect is negligible. However, the effect is present in the right ventricle, as well as in pathological conditions with ineffective autoregulation. The beneficial effect of vascular emptying may be reduced in the presence of a stenosis. Thus cardiac contraction affects vascular diameters thereby reducing coronary inflow and enhancing venous outflow. Emptying of the vasculature, however, enhances muscle contraction. The extracellular matrix exerts its effect mainly on cardiac properties rather than on the cross-talk between cardiac muscle and coronary circulation.
TL;DR: The progress in understanding Ubiquitylation of membrane proteins and its role in endoplasmic reticulum-associated degradation is discussed.
Abstract: Ubiquitylation of membrane proteins has gained considerable interest in recent years. It has been recognized as a signal that negatively regulates the cell surface expression of many plasma membrane proteins both in yeast and in mammalian cells. Moreover, it is also involved in endoplasmic reticulum-associated degradation of membrane proteins, and it acts as a sorting signal both in the secretory pathway and in endosomes, where it targets proteins into multivesicular bodies in the lumen of vacuoles/lysosomes. In this review we discuss the progress in understanding these processes, achieved during the past several years.
TL;DR: A comprehensive overview of the roles of voltage-gated calcium channels and associated subunits in normal and pathological brain activity within the context of idiopathic generalized epilepsy is provided.
Abstract: The idiopathic generalized epilepsies encompass a class of epileptic seizure types that exhibit a polygenic and heritable etiology. Advances in molecular biology and genetics have implicated defects in certain types of voltage-gated calcium channels and their ancillary subunits as important players in this form of epilepsy. Both T-type and P/Q-type channels appear to mediate important contributions to seizure genesis, modulation of network activity, and genetic seizure susceptibility. Here, we provide a comprehensive overview of the roles of these channels and associated subunits in normal and pathological brain activity within the context of idiopathic generalized epilepsy.
TL;DR: Because of the organizing potential of cholesterol in membranes, disturbances in cellular cholesterol transport have implications for a wide variety of human diseases, of which selected examples are given.
Abstract: This review summarizes the mechanisms of cellular cholesterol transport and monogenic human diseases caused by defects in intracellular cholesterol processing. In addition, selected mouse models of disturbed cholesterol trafficking are discussed. Current pharmacological strategies to prevent atherosclerosis are largely based on altering cellular cholesterol balance and are introduced in this context. Finally, because of the organizing potential of cholesterol in membranes, disturbances in cellular cholesterol transport have implications for a wide variety of human diseases, of which selected examples are given.