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The postsynaptic density (PSD) is a postsynaptic membrane specialization at excitatory synapses. The PSD is made of macromolecular multiprotein complexes, which contain a variety of synaptic proteins including membrane, scaffolding, and signaling proteins. By coaggregating with postsynaptic cell adhesion molecules, PSD proteins promote the formation and maturation of excitatory synapses. PSD proteins organize signaling pathways to coordinate structural and functional changes in synapses, and they regulate trafficking and recycling of glutamate receptors, which determines synaptic strength and plasticity. Synaptic activity dynamically regulates the assembly of the PSD through mechanisms including protein phosphorylation, palmitoylation, and protein degradation. PSD proteins associate with diverse motor proteins, suggesting that they function as adaptors linking motors to their specific cargoes.

γ-Amino butyric acid type A (GABA) receptors are the major sites of fast synaptic inhibition in the brain. GABA receptors play an important role in regulating neuronal excitability and in addition have been implicated in numerous neurological disorders. In order to understand synaptic inhibition it is important to comprehend the cellular mechanisms, that neurons utilize to regulate the accumulation and regulation of GABA receptors at postsynaptic inhibitory specializations. Over the past decade a number of GABA receptor interacting proteins have been identified allowing us to further understand the trafficking, targeting and clustering of these receptors as well as the regulation of receptor stability. In the following review we examine the proteins identified as GABA receptor binding partners and other components of the inhibitory postsynaptic scaffold, and how they contribute to the construction of inhibitory synapses and the dynamic modulation of synaptic inhibition.

At chemical synapses, neurotransmitter is released at a restricted region of the presynaptic plasma membrane, called the active zone. At the active zone, a matrix of proteins is assembled, which is termed the presynaptic grid or cytomatrix at the active zone (CAZ). Components of the CAZ are thought to localize and organize the synaptic vesicle cycle, a series of membrane trafficking events underlying regulated neurotransmitter exocytosis. This review is focused on a set of specific proteins involved in the structural and functional organization of the CAZ. These include the multi-domain Rab3-effector proteins RIM1α and RIM2α; Bassoon and Piccolo, two multi-domain CAZ scaffolding proteins of enormous size; as well as members of the CAST/ERC family of CAZ-specific structural proteins. Studies on ribbon synapses of retinal photoreceptor cells have fostered understanding the molecular design of the CAZ. In addition, the analysis of the delivery pathways for Bassoon and Piccolo to presynaptic sites during development has produced new insights into assembly mechanisms of brain synapses during development. Based on these studies, the active zone transport vesicle hypothesis was formulated, which postulates that active zones, at least in part, are pre-assembled in neuronal cell bodies and transported as so-called Piccolo-Bassoon transport vesicles (PTVs) to sites of synaptogenesis. Several PTVs can fuse on demand with the presynaptic membrane to rapidly form an active zone.

Comprehensive analysis of neuromuscular junction formation and recent data on synaptogenesis and long-term potentiation in the central nervous system revealed a number of extracellular matrix (ECM) molecules regulating different aspects of synaptic differentiation and function. The emerging mechanisms comprise interactions of ECM components with their cell surface receptors coupled to tyrosine kinase activities (agrin, integrin ligands, and reelin) and interactions with ion channels and transmitter receptors (Narp, tenascin-R and tenascin-C). These interactions may shape synaptic transmission and plasticity of excitatory synapses either via regulation of entry and postsynaptic expression of transmitter receptors or via control of GABAergic inhibition. The ECM molecules, derived from both neurons and glial cells and secreted into the extracellular space in an activity-dependent manner, may also shape synaptic plasticity through setting diffusion constraints for neurotransmitters, trophic factors and ions.

In the nervous system, interneuronal communication can occur via indirect or direct transmission. The mode of indirect communication involves chemical synapses, in which transmitters are released into the extracellular space to subsequently bind to the postsynaptic cell membrane. Direct communication is mediated by electrical synapses, and will be the focus of this review.

The most prevalent group of electrical synapses are neuronal gap junctions (both terms are used interchangeably in this article), which directly connect the intracellular space of two cells by gap junction channels. The structural components of gap junction channels in the nervous system are connexin proteins, and, as recently identified, pannexin proteins.

Connexin gap junction channels enable the intercellular, bidirectional transport of ions, metabolites, second messengers and other molecules smaller than 1 kD. More than 20 connexin genes have been found in the mouse and human genome. With the cloning of connexin36 (Cx36), a connexin protein with predominantly neuronal expression, the biochemical correlate of electrotonic transmission between neurons was identified. We outline the distribution of Cx36 as well as two other neuronal connexins (Cx57 and Cx45) in the nervous system, describing their spatial and temporal expression patterns. One focus in this review was the retina, as it shows many and diverse electrical synapses whose connexin components have been identified in fish and mammals. In view of the function of neuronal gap junctions, the network of inhibitory interneurons will be reviewed in detail, focussing on the hippocampus.

Although in vivo data on pannexin proteins are still restricted to information on mRNA expression, electrophysiological data and the expression pattern in the nervous system have been included.

Rapid, faithful, and efficient action potential propagation in mammalian axons is a consequence of myelin and clustered channels. Both myelination and node of Ranvier formation require complex intercellular interactions between neurons and glia that result in profound molecular, morphological, and functional changes in each cell type. This review will focus on the molecular and cellular mechanisms that underlie neuron-glia interactions at the node of Ranvier. In particular, the proteins and protein complexes, and how they participate in node of Ranvier formation and maintenance, will be discussed. Traditionally, myelinating glia have been viewed as merely passive players in neuronal function, conferring on the axons they ensheath various electrical properties that facilitate action potential conduction. However, it is now recognized that this view is incomplete. This review will discuss several examples illustrating how myelinating glia actively regulate the excitable properties of axons including the kinds of channels expressed and their subcellular localization.

Endothelial cells lining the blood vessels form a barrier between circulating immune cells and parenchymal tissue. While the molecular mechanisms involved in antigen-independent recruitment of leukocytes into infected tissue have been extensively studied, the mechanisms involving antigen-specific recruitment of T cells into tissue have remained largely elusive. Here I shall review the experimental evidence that endothelial cells function as antigen-presenting cells and in this function contribute first to regulation of immune responses and second, to antigen-specific recruitment of T cells.

T cell activation requires interactions of T cell antigen receptors and peptides presented by major histocompatibility complex molecules in an adhesive junction between the T cell and antigen-presenting cell (APC). Stable junctions with bull's-eye supramolecular activation clusters have been defined as immunological synapses (IS). These structures maintain T cell–APC interaction and allow directed secretion. T cells can also be activated by asymmetric hemisynapses (HS) that allow migration during signal integration. IS and HS dominate in different stages of T cell priming. Optimal effector functions may also depend upon cyclical use of IS and HS.

T cell activation is crucial for the development of specific immune reactions. It requires physical contact between T cells and antigen-presenting cells (APC). Since these cells are initially located at distinct positions in the body, they have to migrate and find each other within secondary lymphoid organs. After encountering each other both cells have to maintain a close membrane contact sufficiently long to ensure successful signaling. Thus, there is the necessity to temporarily synchronize the motile behavior of these cells. Initially, it had been proposed that during antigen recognition, T cells receive a stop signal and maintain a stable contact with APC for several hours when an appropriate APC has been encountered. However, direct cell observation via time-lapse microscopy in vitro and in vivo has revealed a different picture. While long contacts can be observed, many interactions appear to be very short and sequential despite efficient signaling. Thus, two concepts addressing the biophysics of T cell activation have emerged. The single encounter model proposes that after a period of dynamic searching, a T cell stops to interact with one appropriately presenting APC until signaling is completed. The serial encounter model suggests that T cells are able to collect a series of short signals by different APC until a critical activation threshold is achieved. Future research needs to clarify the relative importance of short and dynamic versus long-lived T cell–APC encounters for the outcome of T cell activation. Furthermore, a thorough understanding of the molecular events underlying the observed complex motility patterns will make these phenomena amenable for intervention, which might result in the identification of new types of immune modulating drugs.

Regulation of the cytoskeleton in cells of the haematopoietic system is essential for fulfilling diverse tasks such as migration towards a chemoattractant, phagocytosis or cell–cell communication. This is particularly true for the many types of T cells, which are at the foundation of the adaptive immune system in vertebrates. Deregulation of actin filament turnover is known to be involved in the development of severe immunodeficiencies or immunoproliferative diseases. Therefore, molecular dissection of signalling complexes and effector molecules, which leads to controlled cytoskeletal assembly, has been the focus of immunological research in the last decade.

In the past, cytoskeletal remodelling was frequently understood as the finish line of signalling, while today it becomes increasingly evident that actin and microtubule dynamics are required for proper signal transmission in many processes such as T cell activation. Significant effort is made in many laboratories to further elucidate the contribution of cytoskeletal remodelling to immune function.

The objective of this article is to summarise the current knowledge on how actin and microtubules are reorganised to support the formation of structures as diverse as the immunological synapse and peripheral protrusions during cell migration.