The role of connexin and pannexin containing channels in the innate and acquired immune response

Connexin (Cx) and pannexin (Panx) containing channels – gap junctions (GJs) and hemichannels (HCs) – are present in virtually all cells and tissues. Currently, the role of these channels under physiological conditions is well defined. However, their role in the immune response and pathological conditions has only recently been explored. Data from several laboratories demonstrates that infectious agents, including HIV, have evolved to take advantage of GJs and HCs to improve viral/bacterial replication, enhance inflammation, and help spread toxicity into neighboring areas. In the current review, we discuss the role of Cx and Panx containing channels in immune activation and the pathogenesis of several infectious diseases. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Uncoupled IP3 receptor can function as a Ca2+-leak channel: cell biological and pathological consequences

Ca(2+) release via intracellular release channels, IP(3)Rs (inositol 1,4,5-trisphosphate receptors) and RyRs (ryanodine receptors), is perhaps the most ubiquitous and versatile cellular signalling mechanism, and is involved in a vast number of cellular processes. In addition to this classical release pathway there is limited, but yet persistent, information about less well-defined Ca(2+)-leak pathways that may play an important role in the control of the Ca(2+) load of the endo(sarco)plasmic reticulum. The mechanisms responsible for this 'basal' leak are not known, but recent data suggest that both IP(3)Rs and RyRs may also operate as Ca(2+)-leak channels, particularly in pathological conditions. Proteolytic cleavage or biochemical modification (such as hyperphosphorylation or nitrosylation), for example, occurring during conditions of cell stress or apoptosis, can functionally uncouple the cytoplasmic control domains from the channel domain of the receptor. Highly significant information has been obtained from studies of malfunctioning channels in various disorders; for example, RyRs in cardiac malfunction or genetic muscle diseases and IP(3)Rs in neurodegenerative diseases. In this review we aim to summarize the existing information about functionally uncoupled IP(3)R and RyR channels, and to discuss the concept that those channels can participate in Ca(2+)-leak pathways.     

Molecular diagnostics of medically important bacterial infections

Infectious diseases are common diseases all over the world. A recent World Health Organization report indicated that infectious diseases are now the world's biggest killer of children and young adults. Infectious diseases in non-industrialized countries caused 45% in all and 63% of death in early childhood. In developed countries, the emergence of new, rare or already-forgotten infectious diseases, such as HIV/AIDS, Lyme disease and tuberculosis, has stimulated public interest and inspired commitments to surveillance and control. Recently, it is reported that infectious diseases are responsible for more than 17 million deaths worldwide each year, most of which are associated with bacterial infections. Hence, the control of infectious diseases control is still an important task in the world. The ability to control such bacterial infections is largely dependent on the ability to detect these aetiological agents in the clinical microbiology laboratory. Diagnostic medical bacteriology consists of two main components namely identification and typing. Molecular biology has the potential to revolutionise the way in which diagnostic tests are delivered in order to optimise care of the infected patient, whether they occur in hospital or in the community. Since the discovery of PCR in the late 1980s, there has been an enormous amount of research performed which has enabled the introduction of molecular tests to several areas of routine clinical microbiology. Molecular biology techniques continue to evolve rapidly, so it has been problematic for many laboratories to decide upon which test to introduce before that technology becomes outdated. However the vast majority of diagnostic clinical bacteriology laboratories do not currently employ any form of molecular diagnostics but the use such technology is becoming more widespread in both specialized regional laboratories as well as in national reference laboratories. Presently molecular biology offers a wide repertoire of techniques and permutations of these analytical tools, hence this article wishes to explore the application of these in the diagnostic laboratory setting.     

Meeting report: How to get wrong things right--a discussion over current and future pandemic infectious diseases

Infectious diseases have played a substantial part in shaping the history of humanity. In a discussion at a recent EMBL-EMBO science and society symposium entitled 'The future of our species', several experts discussed how infectious diseases are still influencing our world today. Here we present examples from recent and current infectious disease epidemics followed by a discussion of the local, national and international response to these. Special emphasis is laid on how the change of our environment can augment the world-wide spread of infectious diseases and the role of education in limiting this spread. An urgent need for improved coordinative efforts in globally combating infectious diseases is called for and examples are highlighted.     

Histamine action on vertebrate GABAA receptors: direct channel gating and potentiation of GABA responses

Histamine is not only a crucial cytokine in the periphery but also an important neurotransmitter and neuromodulator in the brain. It is known to act on metabotropic H1-H4 receptors, but the existence of directly histamine-gated chloride channels in mammals has been suspected for many years. However, the molecular basis of such mammalian channels remained elusive, whereas in invertebrates, genes for histamine-gated channels have been already identified. In this report, we demonstrated that histamine can directly open vertebrate ion channels and identified beta subunits of GABA(A) receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric beta channels, histamine evoked currents with an EC(50) of 212 microm (beta(2)) and 174 microm (beta(3)), whereas GABA is only a very weak partial agonist. We tested several known agonists and antagonists for the histamine-binding site of H1-H4 receptors and described for beta channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of alpha(1)beta(2) or alpha(1)beta(2)gamma(2) subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a gamma(2) subunit-controlled manner. Despite the vast number of synthetic modulators of GABA(A) receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABA(A) receptors and may thus represent an endogenous ligand for an allosteric site.     

Neuronal and glial localization of NMDA receptors in the cerebral cortex

The crucial role of glutamate receptors of theN-methyl-d-aspartate (NMDA) type in many fundamental cortical functions has been firmly established, as has its involvement in several neuropsychiatric diseases, but until recently, very little was known of the anatomical localization of NMDA receptors in the cerebral cortex of mammals. The recent application of molecular biological techniques to the study of NMDA receptors has allowed the production of specific tools, the use of which has much increased our understanding of the localization of NMDA receptors in the cerebral cortex. In particular, immunocytochemical studies on the distribution of cortical NMDA receptors have:

1. Demonstrated the preferential localization of NMDA receptors in dendritic spines, in line with previous work;
2. Disclosed a thus far unknown fraction of presynaptic NMDA receptors on both excitatory and inhibitory axon terminals; and
3. Shown that cortical astrocytes express NMDA receptors.

These studies indicate that the effects of cortical NMDA receptor activation are not caused exclusively by the opening of NMDA channels on neuronal postsynaptic membranes, as previously assumed, and that the activation of presynaptic and glial NMDA receptors can contribute significantly to these effects.     

Tandem couture

Receptor subunits in the Cys-loop superfamily assemble to form channels as hom opentamers or heteropentamers, expanding functional diversity through modularity. Expression of two or more compatible subunit types can lead to various receptor assemblies or subtypes. However, what may be good for diversity in vivo may be undesirable for the bench scientist, because we often wish to reduce our analyses to a single receptor subtype. By linking two or more subunits, creating tandems or concatamers, we can control stoichiometry and limit expression to exactly one receptor subtype. In this fashion, receptors with mixed subunit subtypes and heterozygous mutations can be separated from a mixture and can be described in detail. However, several recent studies have shown that this may be more easily conceived than accomplished, because several unforeseen problems have arisen. Concatamers can degrade, linkers can sometimes be clipped after or during translation, and one subunit may “loop out” or even become part of a second (now linked) pentamer with different characteristics. Some strategies have been developed to overcome these drawbacks, and the resultant new information that has begun to emerge has revitalized the study of these receptors in heterologous expression systems.     

New approaches in vaccine development for parasitic infections

Vaccines have had a tremendous impact on the control of infectious diseases. Not only are vaccines potentially the least expensive mechanism to combat infectious diseases, under optimal conditions, widespread vaccination can result in disease eradication - as in the case of smallpox. Despite this great potential, vaccines have had little impact on human parasitic infections. The reasons for this are many - these eukaryotic pathogens are genetically and biologically complex organisms, some with elaborate life cycles and well-honed immune evasion mechanisms. Additionally, our understanding of the mechanisms of immune control of many parasitic infections -- of what constitutes an effective immune response and of how to induce high-quality immunological memory -- is not fully developed. This review attempts to highlight recent advances that could impact vaccine discovery and development in parasitic infections and proposes areas where future studies may lead to breakthroughs in vaccines for the agents of parasitic diseases. There are several other recent reviews highlighting the results of vaccine trials, specifically in the malaria field.     

Insights into the role of Toll-like receptors in modulation of T cell responses

The innate immune receptors, such as Toll-like receptors (TLRs), are intimately involved in the early sensing of invading microorganisms or their structural components. Engagement of TLRs with their ligands results in activation of several downstream intracellular pathways leading to activation of innate and adaptive immune system cells. It was initially thought that TLRs are primarily expressed by antigen-presenting cells (APCs), such as macrophages and dendritic cells, and that interactions between microbial ligands and TLRs in these cells will indirectly result in activation of cells of the adaptive immune system, especially T cells. However, it has now become evident that TLRs are also expressed by various T cell subsets, such as conventional αβT cells, regulatory T cells, and γδT cells as well as natural killer T cells. Importantly, it appears that at least in some of these T cell subsets, TLRs are functionally active, because stimulation of these cells with TLR agonists in the absence of APCs results in exertion of effector or regulatory functions of T cells. The present review attempts to summarize the recent findings related to TLR expression in different T cell subsets and the direct role of TLRs in the induction and regulation of T cell responses, including those responses that occur at mucosal surfaces. In addition, the potential use of TLR agonists for steering T cell responses as a prophylactic or therapeutic strategy in the context of infectious, allergic or autoimmune diseases is explored.     

Tumour necrosis factors in immune regulation: Everything that''s interesting is … New!

Tumour necrosis factors have been classically studied as molecules central to the pathogenesis of infectious, inflammatory and autoimmune diseases. The recent generation of mice deficient in TNFα, LTα, or their receptors, has provided exciting new insights into the physiological role of these molecules in the development of secondary lymphoid tissues and in the organisation of the Immoral immune response.     

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.     

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.     

The ion channels to cytoskeleton connection as potential mechanism of mechanosensitivity

As biological force-sensing systems mechanosensitive (MS) ion channels present the best example of coupling molecular dynamics of membrane proteins to the mechanics of the surrounding cell membrane. In animal cells MS channels have over the past two decades been very much in focus of mechanotransduction research. In recent years this helped to raise awareness of basic and medical researchers about the role that abnormal MS channels may play in the pathophysiology of diseases, such as cardiac hypertrophy, atrial fibrillation, muscular dystrophy or polycystic kidney disease. To date a large number of MS channels from organisms of diverse phylogenetic origins have been identified at the molecular level; however, the structure of only few of them has been determined. Although their function has extensively been studied in a great variety of cells and tissues by different experimental approaches it is, with exception of bacterial MS channels, very little known about how these channels sense mechanical force and which cellular components may contribute to their function. By focusing on MS channels found in animal cells this article discusses the ways in which the connections between cytoskeleton and ion channels may contribute to mechanosensory transduction in these cells. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.     

结核疫苗研究进展

结核病是由结核分枝杆菌感染引起的传染病,是危害人类健康的主要传染病之一。目前被广泛应用的卡介苗对于新生儿和儿童的严重播散性疾病有很好的保护效果,但对于成人活动性结核病的有效性,却存在很大的争议。近年来,人们一直努力研发新疫苗并且已经取得了一些成果。这些新型结核疫苗在临床测试中的结果是非常令人兴奋和鼓舞人心的。但是,我们仍需继续探索新型结核疫苗。     

Fcgamma receptors as regulators of immune responses

In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.     

A-to-I RNA editing modulates the pharmacology of neuronal ion channels and receptors

The regulation of neuronal excitability is complex, as ion channels and neurotransmitter receptors are underlying a large variety of modulating effects. Alterations in the expression patterns of receptors or channel subunits as well as differential splicing contribute to the regulation of neuronal excitability. RNA editing is another and more recently explored mechanism to increase protein diversity, as the genomic recoding leads to new gene products with novel functional and pharmacological properties. In humans A-to-I RNA editing targets several neuronal receptors and channels, including GluR2/5/6 subunits, the Kv1.1 channel, and the 5-HT_2C receptor. Our review summarizes that RNA editing of these proteins does not only change protein function, but also the pharmacology and presumably the drug therapy in human diseases.     

The role of Pannexin-1 channels and extracellular ATP in the pathogenesis of the human immunodeficiency virus

Only recently, the role of large ionic channels such as Pannexin-1 channels and Connexin hemichannels has been implicated in several physiological and pathological conditions, including HIV infection and associated comorbidities. These channels are in a closed stage in healthy conditions, but in pathological conditions including HIV, Pannexin-1 channels and Connexin hemichannels become open. Our data demonstrate that acute and chronic HIV infection induces channel opening (Pannexin and Connexin channels), ATP release into the extracellular space, and subsequent activation of purinergic receptors in immune and non-immune cells. We demonstrated that Pannexin and Connexin channels contribute to HIV infection and replication, the long-term survival of viral reservoirs, and comorbidities such as NeuroHIV. Here, we discuss the available data to support the participation of these channels in the HIV life cycle and the potential therapeutic approach to prevent HIV-associated comorbidities.     

Emerging infectious diseases associated with bat viruses

Bats play important roles as pollen disseminators and pest predators. However, recent interest has focused on their role as natural reservoirs of pathogens associated with emerging infectious diseases. Prior to the outbreak of severe acute respiratory syndrome (SARS), about 60 bat virus species had been reported. The number of identified bat viruses has dramatically increased since the initial SARS outbreak, and most are putative novel virus species or genotypes. Serious infectious diseases caused by previously identified bat viruses continue to emerge throughout in Asia, Australia, Africa and America. Intriguingly, bats infected by these different viruses seldom display clinical symptoms of illness. The pathogenesis and potential threat of bat-borne viruses to public health remains largely unknown. This review provides a brief overview of bat viruses associated with emerging human infectious diseases.     

Receptors coupled to ionic channels: the glutamate receptor family.

Glutamate-gated ion channels belong to a complex family of receptors containing several pharmacological subtypes. They are thought to be essential for the acquisition of associative memory and for activity-dependent synaptogenesis, and have been implicated in several central nervous system diseases. Within the past year, molecular cloning of the first glutamate receptor channel and several related subunits has opened new approaches for understanding the basis of these important phenomena.