Chemoelectrical signal transduction in olfactory sensory neurons of air-breathing vertebrates

When odorants bind to the sensory cilia of olfactory sensory neurons, the cells respond with an electrical output signal, typically a short train of action potentials. This review describes the present state of knowledge about the olfactory signal transduction process. In the last decade, a set of transduction molecules has been identified which help to explain many aspects of the sensory response. Odor-induced second-messenger production, activation of transduction channels, the central role of the ciliary Ca²⁺ concentration, as well as mechanisms that mediate adaptation, are all qualitatively understood on the basis of a consistent scheme for chemoelectrical transduction. This scheme, although necessarily incomplete, can serve as a working model for further experimentation which may reveal kinetical aspects of signal transduction processes in olfactory sensory neurons.     

T-cell signal transduction and the role of protein kinase C

The T lymphocyte has a vital part to play in maintaining the host response to bacterial and viral infection and also appears to play a key pathological role in autoimmune diseases such as rheumatoid arthritis. In this review, we summarize the signalling pathways which trigger antigen-driven T-cell proliferation and examine the evidence which suggests that protein kinase C (PKC) is fundamental to this process. Finally, we discuss the therapeutic potential that PKC inhibitors may have in the treatment of autoimmune disease. Received 31 March 1998; received after revision 19 May 1998; accepted 19 May 1998     

The role of endocytosis in activating and regulating signal transduction

Endocytosis is increasingly understood to play crucial roles in most signaling pathways, from determining which signaling components are activated, to how the signal is subsequently transduced and/or terminated. Whether a receptor-ligand complex is internalized via a clathrin-dependent or clathrin-independent endocytic route, and the complexes' subsequent trafficking through specific endocytic compartments, to then be recycled or degraded, has profound effects on signaling output. This review discusses the roles of endocytosis in three markedly different signaling pathways: the Wnt, Notch, and Eph/Ephrin pathways. These offer fundamentally different signaling systems: (1) diffusible ligands inducing signaling in one cell, (2) membrane-tethered ligands inducing signaling in a contacting receptor cell, and (3) bi-directional receptor-ligand signaling in two contacting cells. In each of these systems, endocytosis controls signaling in fascinating ways, and comparison of their similarities and dissimilarities will help to expand our understanding of endocytic control of signal transduction across multiple signaling pathways.     

Syntrophin proteins as Santa Claus: role(s) in cell signal transduction

Syntrophins are a family of cytoplasmic membrane-associated adaptor proteins, characterized by the presence of a unique domain organization comprised of a C-terminal syntrophin unique (SU) domain and an N-terminal pleckstrin homology (PH) domain that is split by insertion of a PDZ domain. Syntrophins have been recognized as an important component of many signaling events, and they seem to function more like the cell’s own personal ‘Santa Claus’ that serves to ‘gift’ various signaling complexes with precise proteins that they ‘wish for’, and at the same time care enough for the spatial, temporal control of these signaling events, maintaining overall smooth functioning and general happiness of the cell. Syntrophins not only associate various ion channels and signaling proteins to the dystrophin-associated protein complex (DAPC), via a direct interaction with dystrophin protein but also serve as a link between the extracellular matrix and the intracellular downstream targets and cell cytoskeleton by interacting with F-actin. They play an important role in regulating the postsynaptic signal transduction, sarcolemmal localization of nNOS, EphA4 signaling at the neuromuscular junction, and G-protein mediated signaling. In our previous work, we reported a differential expression pattern of alpha-1-syntrophin (SNTA1) protein in esophageal and breast carcinomas. Implicated in several other pathologies, like cardiac dys-functioning, muscular dystrophies, diabetes, etc., these proteins provide a lot of scope for further studies. The present review focuses on the role of syntrophins in membrane targeting and regulation of cellular proteins, while highlighting their relevance in possible development and/or progression of pathologies including cancer which we have recently demonstrated.     

Interferon receptors and their role in interferon action

Interferon (IFN) proteins interact with cells through specific cell surface receptors, some of which have been purified and cloned. The alpha-IFNs and beta-IFN bind to a common receptor (type I), whereas gamma-IFN binds to a separate receptor (type II). Both types of high-affinity receptors have been demonstrated on a variety of receptors and the ways in which IFNs may affect cellular physiology and gene expression is discussed.     

Interferon receptors and their role in interferon action

Summary Interferon (IFN)_proteins interact with cells through specific cell surface receptors, some of which have been purified and cloned. The alpha-IFNs and beta-IFN bind to a common receptor (type I), whereas gamma-IFN binds to a separate receptor (type II). Both types of high-affinity receptors have been demonstrated on a variety of different kinds of cells but in relatively low numbers (10²–10⁴/cell). The relationship between IFN binding to receptors and the ways in which IFNs may affect cellular physiology and gene expression is discussed.     

Plexins: axon guidance and signal transduction

Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as semaphorins, ephrins and netrin. Plexins function as receptors for the repulsive axonal guidance molecules semaphorins. Intracellular domains of plexins are responsible for initiating cellular signal transduction inducing axon repulsion. Recent advances have revealed molecular mechanisms for plexin-mediated cytoskeletal reorganization, leading to repulsive responses, and small GTPases play important roles in this signaling. Plexin-B1 activates Rho through Rho-specific guanine nucleotide exchange factors, leading to neurite retraction. Plexin-B1 possesses an intrinsic GTPase-activating protein activity for R-Ras and induces growth cone collapse through R-Ras inactivation. In this review we survey current understanding of the signaling mechanisms of plexins.Received 13 January 2005; received after revision 3 February 2005; accepted 15 February 2005     

On the ORigin of smell: odorant receptors in insects

Olfaction, the sense of smell, depends on large, divergent families of odorant receptors that detect odour stimuli in the nose and transform them into patterns of neuronal activity that are recognised in the brain. The olfactory circuits in mammals and insects display striking similarities in their sensory physiology and neuroanatomy, which has suggested that odours are perceived by a conserved mechanism. Here I review recent revelations of significant structural and functional differences between the Drosophila and mammalian odorant receptor proteins and discuss the implications for our understanding of the evolutionary and molecular biology of the insect odorant receptors. Received 23 March 2006; accepted 28 April 2006     

The role of chemokines and their receptors in angiogenesis

Chemokines are a vertebrate-specific group of small molecules that regulate cell migration and behaviour in diverse contexts. So far, around 50 chemokines have been identified in humans, which bind to 18 different chemokine receptors. These are members of the seven-transmembrane receptor family. Initially, chemokines were identified as modulators of the immune response. Subsequently, they were also shown to regulate cell migration during embryonic development. Here, we discuss the influence of chemokines and their receptors on angiogenesis, or the formation of new blood vessels. We highlight recent advances in our understanding of how chemokine signalling might directly influence endothelial cell migration. We furthermore examine the contributions of chemokine signalling in immune cells during this process. Finally, we explore possible implications for disease settings, such as chronic inflammation and tumour progression.     

The odd couple: signal transduction and endocytosis

Cell surface receptors are used to transmit extracellular information. The activation of cell surface receptors initiates signal transduction and receptor endocytosis. Signal transduction and the endosomal transport of activated receptors require precise regulation. New concepts for the integration of endocytosis and signaling arise from recent findings that suggest bidirectional interplay of these two processes. This review discusses the following questions: (i) do activated cell surface receptors modify the endosomal system to promote internalization and endosomal traffic, and (ii) do internalized cell surface receptors use specifically localized signaling complexes to generate specific biological signals?     

Odor maps in the brain: Spatial aspects of odor representation in sensory surface and olfactory bulb

The olfactory sense detects and distinguishes a multitude of different odors. Recent progress in molecular as well as physiological approaches has elucidated basic principles of neuronal encoding of odorants, common to insects and vertebrates. The construction of neuronal representations for odors begins with the task of mapping the multidimensional odor space onto the two-dimensional sensory surface, and subsequently onto the olfactory bulb or antennal lobe. A distributed expression of odorant receptors, albeit restricted to subregions of the sensory surface (large, intermediate or small for zebrafish, mouse or drosophila, respectively), ensures a robust representation, insensitive to mechanical insult. Olfactory receptor neurons expressing the same odorant receptors converge to form a receptotopic map in the olfactory bulb or antennal lobe. The emerging coding principle is a chemotopic representation of odorants at the first brain level, realized either as combinatorial or as monospecific representation, depending on the odorant.     

Angiogenesis and signal transduction in endothelial cells

Endothelial cells receive multiple information from their environment that eventually leads them to progress along all the stages of the process of formation of new vessels. Angiogenic signals promote endothelial cell proliferation, increased resistance to apoptosis, changes in proteolytic balance, cytoskeletal reorganization, migration and, finally, differentiation and formation of a new vascular lumen. We aim to review herein the main signaling cascades that become activated in angiogenic endothelial cells as well as the opportunities of modulating angiogenesis through pharmacological interference with these signaling mechanisms. We will deal mainly with the mitogen-activated protein kinases pathway, which is very important in the transduction of proliferation signals; the phosphatidylinositol-3-kinase/protein kinase B signaling system, particularly essential for the survival of the angiogenic endothelium; the small GTPases involved in cytoskeletal reorganization and migration; and the kinases associated to focal adhesions which contribute to integrate the pathways from the two main sources of angiogenic signals, i.e. growth factors and the extracellular matrix.Received 13 February 2004; received after revision 25 March 2004; accepted 19 April 2004     

ROPs in the spotlight of plant signal transduction

Small guanine nucleotide binding proteins of the Rho family called ROP play a crucial role as regulators of signal transduction in plants. They participate in pathways that influence growth and development, and the adaptation of plants to various environmental situations. As members of the Ras superfamily, ROPs function as molecular switches cycling between a GDP-bound ‘off’ and a GTP-bound ‘on’ state in a strictly regulated manner. Latest research provided fascinating new insights into ROP regulation by novel guanine nucleotide exchange factors, unconventional GTPase activating proteins, and guanine nucleotide dissociation inhibitors, which apparently organize localized ROP activation. Important progress has also been made concerning signaling components upstream and downstream of the ROP cycle involving receptor-like serine/threonine kinases and effectors that can manipulate cytoskeletal dynamics, intracellular calcium levels, H₂O₂ production and further cellular targets. This review outlines the fast developing knowledge on ROP GTPases highlighting their specific features, regulation and roles in a cellular signaling context. Received 28 April 2006; received after revision 2 June 2006; accepted 29 June 2006     

Visualizing odor representation in the brain: a review of imaging techniques for the mapping of sensory activity in the olfactory glomeruli

The brain transforms clues from the external world, the sensory stimuli, into activities in neuroglial networks. These circuits are activated in specialized sensory cortices where specific functional modules are responsible for the spatiotemporal coding of the stimulus. A major challenge in the neuroscience field has been to image the spatial distribution and follow the temporal dynamics of the activation of such large populations in vivo. Functional imaging techniques developed in the last 30 years have enabled researchers to solve this critical issue, and are reviewed here. These techniques utilize sources of contrast of radioisotopic, magnetic and optical origins and exploit two major families of signals to image sensory activity: the first class uses sources linked to cellular energy metabolism and hemodynamics, while the second involves exogenous indicators of neuronal activity. The whole panel of imaging techniques has fostered the functional exploration of the olfactory bulb which is one of the most studied sensory structures. We summarize the major results obtained using these techniques that describe the spatial and temporal activity patterns in the olfactory glomeruli, the first relay of olfactory information processing in the main olfactory bulb. We conclude this review by describing promising technical developments in optical imaging and future directions in the study of olfactory spatiotemporal coding.     

Prolactin and growth hormone signal transduction in lymphohaemopoietic cells

The peptide hormones, prolactin (PRL) and growth hormone (GH), are known to regulate numerous target tissues. Among such targets are cells of the immune system, including T cells, B cells, macrophages and natural killer cells. We have cloned a panel of PRL- and GH-inducible T cell genes for use in studies to understand how these hormones through the expression of these genes modulate the biology of immune function cells. This article focuses on the signalling pathways emanating from the PRL receptor (PRL-R) and GH receptor (GH-R), and the expression of PRL-inducible target genes.     

Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization

The vertebrate olfactory system recognizes and discriminates between thousands of structurally diverse odorants. Detection of odorants in mammals is mediated by olfactory receptors (ORs), which comprise the largest superfamily of G protein-coupled receptors (GPCRs). Upon odorant binding, ORs couple to G proteins, resulting in an increase in intracellular cAMP levels and subsequent receptor signaling. In this review, we will discuss recently published studies outlining the molecular basis of odor discrimination, focusing on pharmacology, G protein activation, and desensitization of ORs. A greater understanding of the molecular mechanisms underlying OR activity may help in the discovery of agonists and antagonists of ORs, and of GPCRs with potential therapeutic applications.