Trends in Pharmacological Sciences

Published by Elsevier
Online ISSN: 0165-6147
Publications
Harvesting of cell contents from a neurone situated within a 300 m brain slice. (a) The patchclamp electrode has been placed on the surface of the neurone and the whole-cell recording configuration is formed. (b) The application of gentle negative pressure results in the collection of the cytoplasm and importantly mRNA species therein, into the patch-pipette. (c) The electrode has been withdrawn from the neurone and taken out of the brain slice with subsequent formation of a nucleated patch, thus preventing loss or contamination of the sample. (d) Withdrawal of the nucleated patch through the air-electrolyte interface results in the loss of the nucleated patch integrity. Scale bar: 10 m.
Three-prime-end amplification (TPEA)-generated expression profiles of two rat striatal acetylcholine-containing interneurones. The presence of neurotrophin trkA, trkB and trkC receptors, tachykinin NK 1 , NK 2 and NK 3 receptors, adenosine A 1 , A 2A , A 2B and A 3 receptors, AMPA receptor subunits GluR1-4, NMDA receptor subunits NR1 and NR2A-D, and Na channel subunits VNaI-III and VNaVI is shown. In this particular example, contamination of the patch-clamp electrode by other neurones in the brain slice was assessed by detection of mRNA encoding preproenkephalin (preproenk), preprotachykinin (preprotach) and preprosomatostatin (preprosom), which are expressed in high abundance by 90% of the nonacetylcholine-containing striatal neurones. Contamination with genomic DNA was controlled for using PCR primers for two polymorphic repeat sequences (genomic 1 and 2). To control for the efficiency of the sampling and pre-amplification procedures, neurones were assessed for the expression of at least four housekeeping genes [-tubulin, -actin, ribosomal protein (RP) L11 and synaptotagmin 1] in addition to choline acetyltransferase (ChAT), which synthesizes acetylcholine, and glutamate decarboxylase (GAD) 67. These profiles demonstrate the range of non-homologous genes that can be analysed by such global pre-amplification approaches; in this instance, the observed expression of each gene can be correlated to functional observations. Figure is reproduced, with permission, from Ref. 15.
Article
The manner in which a cell responds to and influences its environment is ultimately determined by the genes that it expresses. To fully understand and manipulate cellular function, identification of these expressed genes is essential. Techniques such as RT-PCR enable examination of gene expression at the tissue level. However, the study of complex heterogeneous tissue, such as the CNS or immune system, requires gene analysis to be performed at much higher resolution. In this article, the various methods that have been developed to enable RT-PCR to be performed at the level of the single cell are reviewed. In addition, how, when carried out in combination with techniques such as patch-clamp recording, single-cell gene-expression studies extend our understanding of biological systems is discussed.
 
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Recent models of receptor function raise issues about the conformations of their coupling to G proteins
 
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Smooth muscle is activated by plasma-membrane-acting agonists that induce inositol (1,4,5)-trisphosphate [Ins(1,4,5)P(3)] to release Ca(2+) from the intracellular sarcoplasmic reticulum (SR) Ca(2+) store. Increased concentrations of agonist evoke a concentration-dependent graded release of Ca(2+) in a process called 'quantal' Ca(2+) release. Such a graded release seems to be incompatible with both the finite capacity of the SR store and the positive-feedback Ca(2+)-induced Ca(2+) release (CICR)-like process that is operative at Ins(1,4,5)P(3) receptors, which - once activated - might be expected to deplete the entire store. Proposed explanations of quantal release include the existence of multiple stores, each with different sensitivities to Ins(1,4,5)P(3), or Ins(1,4,5)P(3) receptor opening being controlled by the Ca(2+) concentration within the SR. Here, we suggest that the regulation of Ins(1,4,5)P(3) receptors by the Ca(2+) concentration within the SR explains the quantal Ca(2+)-release process and the apparent existence of multiple Ca(2+) stores in smooth muscle.
 
Article
Receptor-mediated activation of phospholipase C to generate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a ubiquitous signalling pathway in mammalian systems. A family of three IP3 receptor subtype monomers form functional tetramers, which act as effectors for Ins(1,4,5)P3, providing a ligand-gated channel that allows Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P3 is considered to be a second messenger that mobilizes Ca2+ from intracellular stores. Ca2+ store mobilization by Ins(1,4,5)P3 can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP3 receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 receptor pharmacology, with particular emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agonists and antagonists is also discussed.
 
Article
Three isoforms of the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptor have been identified. Each receptor isoform has been functionally characterized using many different techniques. Although these receptor isoforms possess high homology, interesting differences in their Ca2+ dependence, Ins(1,4,5)P3 sensitivity and subcellular distribution exist, implying distinct cellular roles. Indeed, interplay among the isoforms might be necessary for a cell to control spatial and temporal aspects of cytosolic Ca2+ signals, which are important for many cellular processes. In this review isoform-specific functions, primarily at the single-channel level, will be highlighted and these properties will be correlated with Ca2+ signals in intact cells.
 
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The continuing rapid progress towards a complete database of structural information on the human genome creates a challenge of ensuring that current schemes for classifying and naming receptors and ion channels effectively integrate this information with functional data to provide unambiguous principles for classification. In this article, Paul Hartig and colleagues review the recent deliberations of the Serotonin Club Nomenclature Committee and outline a number of its recommendations aimed at encouraging consistency in current and future receptor nomenclature. Based on these principles, the present classification of 5-HT1B and 5-HT1D receptors is reconsidered, and a revised nomenclature for 5-HT1B, 5-HT1D alpha and 5-HT1D beta receptor subtypes is suggested.
 
Article
Following the first report on the identification of endothelin (ET), an increasing body of work has accumulated on this endothelium-derived 21-amino acid vasoconstrictor peptide. Subsequently, the existence of three distinct isoforms of ET, designated ET-1, ET-2 and ET-3, was predicted from the finding of three separate genes. The differential potencies of the three isoforms of the ET family have opened up the possibility of the existence of multiple ET receptor subtypes. Recently, molecular biological techniques provided direct evidence of at least two distinct subtypes of ET receptor. This article discusses the functions of the ETs, focusing especially on the molecular characteristics of their receptors.
 
Article
There is strong evidence for the existence of Gq/11-coupled dopamine receptors in the brain but the mechanism by which dopamine signaling activates Gq/11, or its roles in neuronal function, are only just beginning to be understood. The importance of such a pathway is underlined by putative links between dopamine-regulated phosphoinositide signaling and several central nervous system disorders that include schizophrenia, addiction and Parkinson's disease.
 
Article
Glucuronidation is an important process in the metabolism of xenobiotic and endogenous substances leading to enhancement of excretion of these compounds from the body. A multigene family encodes a number of UDP-glucuronosyltransferase enzymes which catalyse this route of metabolism. Recent advances in biochemical and molecular biological approaches, reviewed here by Thomas Tephly and Brian Burchell, have given new insight into the function and structure of UDP-glucuronosyltransferases. These proteins have surprising similarities and yet appear to be capable of conjugating a remarkable number of different chemicals.
 
Article
Approaches that allow ligand occupancy of a wide range of G protein-coupled receptors to be converted into robust assays amenable to relatively high-throughput analysis are ideal for screening for novel ligands at this class of receptor. Many attempts have been made to design universal ligand-screening systems such that any GPCR can be screened using a common assay end-point. Manipulation of the G protein within the assay system offers the possibility of achieving this. To better understand the domains involved in the interactions between G protein-coupled receptors, G proteins and effector polypeptides and the fine details of these contacts, a wide range of chimaeric G protein alpha subunits have been produced. Graeme Milligan and Stephen Rees discuss the information generated by such studies and the ways in which such chimaeric G proteins can be integrated into assay systems for drug discovery.
 
Article
Avoiding drug-induced cardiac arrhythmia is recognized as a major hurdle in the successful development of new drugs. The most common problem is acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K(+) channels, delay cardiac repolarization and increase the risk of torsades de pointes arrhythmia (TdP). Not all hERG channel blockers induce TdP because they can also modulate other channels that counteract the hERG channel-mediated effect. However, hERG channel blockade is an important indicator of potential pro-arrhythmic liability. The molecular determinants of hERG channel blockade have been defined using a site-directed mutagenesis approach. Combined with pharmacophore models, knowledge of the drug-binding site of hERG channels will facilitate in silico design efforts to discover drugs that are devoid of this rare, but potentially lethal, side-effect.
 
Article
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
 
Article
Current understanding of drug abuse has been greatly influenced by the emphasis on drug-seeking behaviour as the common element. The three main attributes of drugs that maintain, direct and regulate drug-seeking behaviour are their positively reinforcing and discriminative and aversive stimulus properties. Each process may be analysed in terms of underlying behavioural and neural mechanisms that are mutually complementary and interactive. Environmental stimuli conditioned to the effects of the drugs also play a key role in eliciting and maintaining drug-seeking behaviour. Both the behavioural and the neural mechanisms are subject to modulating variables such as social, environmental and genetic factors, including the previous behavioural and pharmacological history of the individual. Thus, the behavioural approach to addiction does not preclude important roles for other factors, but rather seeks to integrate them into a comprehensive theoretical framework strongly linked to empirical data.
 
Article
Recruitment of inflammatory leukocytes to the injured spinal cord is a physiological response that is associated with the production of cytokines and proteinases that are involved in host defense and wound repair. Cells in the spinal cord are mainly post-mitotic and tissue regeneration is poor; thus, these inflammatory mediators can exacerbate the damage to spared tissue and thereby impair spontaneous functional recovery. Although several aspects of immune function might benefit the CNS, experimental studies indicate that acute neuroinflammation aggravates tissue injury. Until the timing and nature of the molecular signals that govern leukocyte recruitment and activation after spinal injury are defined, clinical therapies designed to boost immune cell function should be avoided.
 
Article
The application of modern molecular biological methods has had an increasing and dramatic impact upon the discipline of molecular neuropharmacology. This is particularly true for the study of neurotransmitter receptors, where the use of recombinant DNA techniques has resulted in the cloning of multiple and sometimes unexpected receptor subtypes for a given neurotransmitter and, in some cases, the cloning of receptors for which no neurotransmitter is known. Within the past couple of years, it has become readily apparent that dopamine receptors will be no exception to this trend. Five different dopamine receptors have now been cloned and identified using molecular biological techniques, while only a few years ago only two receptor subtypes were thought to exist. David Sibley and Frederick Monsma review the molecular characteristics of the recently cloned dopamine receptors and discuss prospects for the cloning and identification of additional subtypes in this receptor family.
 
Article
Adenosine is able to decrease the release of most neurotransmitters. This is consistent with its general role in adjusting the rate of energy consumption to the metabolic supply in a tissue. Bertil Fredholm and Tom Dunwiddie discuss the mechanisms behind the presynaptic inhibitory action of adenosine. By stimulating receptors similar to A1-receptors, adenosine can inhibit adenylate cyclase, open K+ channels and reduce flux through Ca2+ channels. It is suggested that adenosine may depress transmitter release in several ways and that the relative importance of these presynaptic actions may vary between nerve terminals.
 
Article
Upregulation of binding to nicotinic acetylcholine receptors (nAChRs) is observed in the brains of both smokers and animals chronically exposed to nicotine, although whether this in vivo change is accompanied by an increase in receptor function is unknown. In vitro recordings indicate that alpha4beta2- and alpha7-subtypes of nAChRs, which are the most abundant subtypes in the brain, are functionally upregulated following prolonged exposure to nicotine. The possible consequences of functional upregulation for nicotine addiction are discussed. Moreover, we propose a new paradigm that describes the unusual behavior of these neuronal nAChRs and helps to explain the effects of nicotine in the CNS and the diffuse effects of ACh.
 
Article
Thapsigargin is the most widely used inhibitor of the ubiquitous sarco-endoplasmic reticulum Ca(2+)-ATPases in mammalian cells. Over the past ten years, this guaianolide compound of plant origin has become a popular tool in a host of studies directed at elucidating the mechanisms of intracellular Ca2+ signalling. Its remarkable potency and selectivity have been instrumental in widening our view of the function of intracellular Ca2+ stores to include such key aspects as store-operated Ca2+ entry or the involvement of the stores in protein synthesis or cell growth. In this article Marek Treiman, Casper Caspersen and Søren Brøgger Christensen review the key pharmacological features of thapsigargin action; they also discuss some of the ways in which its unique properties have shown to be important for obtaining new insights into the biology of Ca2+ stores, and how these properties might encompass a therapeutic potential. In parallel, attention is drawn to some of the limitations and pitfalls encountered when working with thapsigargin.
 
Article
Recent studies using agonist analogues of ATP and other nucleotides have generated some surprising observations which may have ramifications for the classification of P2 receptors, particularly for those responses currently attributed to P2Y receptor activation. 2-MethylthioATP (2-MeSATP), the conventional P2Y receptor agonist, does not interact with ATP in the expected fashion in various models of endothelial function, suggesting that it acts by a different mechanism. Furthermore, in certain cell types where responses to ATP are mediated by phospholipase C activation, 2-MeSATP has little or no activity. Interestingly, the pyrimidine uridine triphosphate (UTP) invariably shows similar potency to ATP in systems where 2-MeSATP is inactive. In this article Steve O'Connor and colleagues discuss these data and their significance, and propose that separate receptors may be responsible: one sensitive to 2-MeSATP and the other, a 'nucleotide' receptor, sensitive to UTP.
 
Article
The glycine site on the NMDA receptor complex has generated an enormous amount of interest since it was first described five years ago. In this review by John Kemp and Paul Leeson the structure-activity relationships of agonists, partial agonists and antagonists acting at the glycine site are reviewed, along with what has been learned from studies with these compounds about the role of this site in physiological and pathological processes. Studies with prototype antagonists, and low-efficacy partial agonists that penetrate the brain, show that these compounds possess anticonvulsant and neuroprotective properties but lack some of the side-effects of other types of NMDA antagonists.
 
Article
The revised 5-HT receptor nomenclature published here was established by the Serotonin Club Receptor Nomenclature Committee and approved by IUPHAR. The members of the Serotonin Club Receptor Nomenclature Committee are: P. B. Bradley, T. A. Branchek, D. E. Clarke, M. L. Cohen, J. R. Fozard, M. Gothert, J. P. Green, P. R. Hartig, D. Hoyer, P. P. A. Humphrey J. E. Leysen, G. R. Martin, D. N. Middlemiss, E. J. Mylecharane, S. J. Peroutka and P. R. Saxena.
 
Article
CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH-cell subsets and illustrate some clinical situations where this may be beneficial.
 
Article
Neurotransmission, which represents chemical signalling between neurons, usually takes place at highly differentiated anatomical structures called synapses. To fulfill both the time and space confinements required for optimal neurotransmission, highly specialized proteins, known as transporters or uptake sites, occur and operate at the presynaptic plasma membrane. Using the energy provided by the Na+ gradient generated by the Na+/K(+)-transporting ATPase, these transporters reuptake the neurotransmitters soon after their release, thereby regulating their effective concentrations at the synaptic cleft and the availability of neurotransmitters for a time-dependent activation of both pre- and postsynaptic receptors. The key role these proteins play in normal neurotransmission is further emphasized when the physiological and social consequences of drugs that interfere with the function of these transporters, such as the psychostimulants (e.g. amphetamine and cocaine) or the widely prescribed antidepressant drugs, are considered. In this review, Bruno Giros and Marc Caron elaborate on the potential consequences of the recent molecular cloning of the dopamine and related transporters and summarize some of the interesting properties that are emerging from this growing family of Na(+)- and Cl(-)-dependent transporters.
 
Article
Preliminary data presented at conferences and in the patent literature introduced the possibility the orphan receptor GPR55 might account for some of the well-documented non-CB(1), non-CB(2) effects reported for certain cannabinoid ligands. Several peer-reviewed publications have recently emerged in which the pharmacology of the cannabinoids at GPR55 has been probed in more depth. Despite this, the classification of GPR55 as a cannabinoid receptor remains a contentious issue. The weight of evidence points to GPR55 as a receptor that is activated by certain cannabinoid ligands and by the bioactive lipid l-alpha-lysophosphatidylinsoitol. It couples to G(12) proteins, activates RhoA and mobilizes intracellular Ca(2+), possibly in an agonist- and tissue-dependant manner, thus displaying 'agonist functional selectivity'. Here, I review the recent literature in an effort to glean the key controversies and outstanding questions surrounding the interaction between cannabinoids and this orphan receptor.
 
Article
Several recent reports describe the efficacy of the hematopoietic factor granulocyte-colony-stimulating factor (G-CSF) in models of stroke and neurodegeneration. Here, we discuss the role of G-CSF as a novel type of multifactorial drug with which to treat stroke, and describe aspects of its modes of action in stroke, in addition to the relationship between clinical trials and the preclinical dataset. Neuroprotective activity in stroke models seems to be based on a direct anti-apoptotic activity in neurons that is mediated by the neuronally expressed G-CSF receptor. Explanations for the long-term effects that improve recovery in different experimental models of stroke include the enhancement of neurogenesis in the adult brain and the stimulation of blood vessel formation. Additional beneficial effects might be based on systemic influences on immunocompetence and inflammation parameters, and the activation of bone-marrow-derived stem cells. Several clinical trials have been initiated in stroke patients, mainly to demonstrate the safety of G-CSF in this setting.
 
Article
Due to the adverse health consequences related to smoking, it is important to understand factors that contribute to nicotine dependence. The most replicated genetic finding for nicotine dependence points to variants on chromosome 15, which includes the alpha5-alpha3-beta4 nicotinic receptor gene cluster. A compelling functional variant is a polymorphism, rs16969968, which alters an amino acid in the alpha5 nicotinic receptor subunit. Several prominent studies report that the replicated nicotine dependence locus also influences the risk for lung cancer and chronic obstructive pulmonary disease. This represents an exciting convergence of genetic findings, and highlights the potential for research on smoking to inform public health.
 
Article
Massive activation of glutamate receptors can result in excessive rises in cytoplasmic Ca2+ that are thought to underlie the fundamental processes ultimately leading to neuronal death. Preventing such cellular Ca2+ rises in the brain may reduce considerably the neuronal damage produced by stroke, head trauma, or epilepsy. Activation of NMDA receptors is instrumental in this type of neurotoxicity. Recent findings, discussed here by Istvan Mody and John MacDonald, indicate that a large proportion of the neurotoxic Ca2+ that enters nerve cells following NMDA receptor activation originates from an intracellular Ca2+ pool. The release of Ca2+ from this pool is sensitive to the skeletal muscle relaxant dantrolene, and this may constitute a novel and alternative therapeutic approach against NMDA receptor-mediated excitotoxicity.
 
Article
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
 
Article
There is evidence to suggest that receptors with seven transmembrane domains can exist in G protein-activating conformations. It is not known how many activated receptor forms exist for each receptor. Furthermore, if there are multiple forms, does the chemical structure of the agonist determine which form dominates, and therefore, which response pathway is activated? This latter scheme is referred to as agonist-receptor trafficking, and is discussed in this, the second of two articles by Terry Kenakin. One way to approach these questions is to study receptors that couple to more than one G protein and, in essence, to try to allow the G protein to indicate the receptor state.
 
Article
Over the past few years, the concept that the activation of G protein-coupled receptors and transmitter-gated ion channels depends on a conformational change has received increasingly widespread acceptance. As a result, these two structurally distinct families of receptors can now be considered to obey a similar two-state mechanism. However, traditional receptor theory has largely overlooked this concept. In this article, Paul Leff explains and illustrates the predictions of the two-state model of receptor activation and discusses its impact on the analysis and interpretation of agonist-receptor interactions.
 
Article
Identification of natural ligands for orphan G-protein-coupled receptors will help expand the boundaries of physiology and pharmacology. Powerful approaches are needed that can pair biologically active ligands with their corresponding receptors. Many attempts have been made to set up universal screening schemes such that receptor activation by its cognate ligand is transduced into a common intracellular signal that is amenable to high-throughput screening analysis. One possibility that achieves such a 'universal assay' takes advantage of the promiscuous nature of the G-protein subunit Galpha16. However, a truly critical look at Galpha16 is still required. In this article, the strengths, weaknesses, problems and pitfalls that are associated with the use of Galpha16 will be discussed, and suggestions of how problems might be overcome with an optimized universal G-protein system will be proposed.
 
Article
Purinergic signalling is now recognized to be involved in a wide range of activities of the nervous system, including neuroprotection, central control of autonomic functions, neural-glial interactions, control of vessel tone and angiogenesis, pain and mechanosensory transduction and the physiology of the special senses. In this article, I give a personal retrospective of the discovery of purinergic neurotransmission in the early 1970s, the struggle for its acceptance for approximately 20 years, the expansion into purinergic cotransmission and its eventual acceptance when receptor subtypes for ATP were cloned and characterized and when purinergic synaptic transmission between neurons in the brain and peripheral ganglia was described in the early 1990s. I also discuss the current status of the field, including recent interest in the pathophysiology of purinergic signalling and its therapeutic potential.
 
Article
Several of the established alpha 1-, alpha 2- and beta-adrenoceptors have now been isolated and cloned. The in situ hybridization method has been used to map the distribution of many of these adrenoceptors within cells of the CNS. These studies add complementary and new information to our knowledge of adrenoceptor localization provided previously by radioligand-mediated autoradiography. Neuronal cell groups containing one or more mRNAs for seven adrenoceptor subtypes throughout the rat CNS have been mapped. In the present review Anthony Nicholas, Tomas Hökfelt and Vincent Pieribone will examine these localizations and discuss the additional information these maps supply, as well as some implications for understanding central noradrenaline and adrenaline systems.
 
Article
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Article
Polyamines are found in every cell of the body and the intricate enzymatic reactions responsible for their metabolism and transport in mammalian cells are now well understood. Despite intense efforts, elucidation of the role of polyamines has suffered in that little information of physiological relevance has surfaced. Recently, recombinant receptor techniques and increased availability of polyamine analogues have revealed, as discussed here by David Johnson, modulation of NMDA receptors by polyamines by reversal of tonic proton inhibition, and a function for these compounds as 'intrinsic rectifier factors' for K+ channels.
 
Article
Interleukin (IL)-17 (now synonymous with IL-17A) is an archetype molecule for an entire family of IL-17 cytokines. Currently believed to be produced mainly by a specific subset of CD4 cells, named Th-17 cells, IL-17 is functionally located at the interface of innate and acquired immunity. Specifically, it induces the release of chemokines and growth factors from mesenchymal cells and is now emerging as an important local orchestrator of neutrophil accumulation in several mammalian organs. Furthermore, there is growing evidence that targeting IL-17 signaling might prove useful in a variety of diseases including asthma, Crohn's disease, multiple sclerosis, psoriatric disease and rheumatoid arthritis. Here, we summarize the key aspects of the biology of IL-17 in mammals and scrutinize the potential pharmacological use of targeting IL-17 in humans.
 
Article
It is generally accepted that muscle wasting is caused by an increase in protein breakdown which seems to be associated with an ATP-dependent, non-lysosomal proteolytic system based on conjugation of proteins to the small polypeptide ubiquitin. Increases in ubiquitin conjugates and in ubiquitin mRNAs are found in the skeletal muscle of experimental animals with various pathological conditions such as infection, acidosis or cancer cachexia. In this review, Josep Argilés and Francisco López-Soriano discuss the role of the ubiquitin-dependent proteolytic pathway in muscle weight loss in pathological situations.
 
Article
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
 
Article
The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed.
 
Article
Agonist stimulation of G protein-coupled receptors causes a dramatic reorganization of their intracellular distribution. Activation of receptors triggers receptor endocytosis and, since receptors recycle back to the surface continuously, a new steady state is reached where a significant proportion of receptors is located internally. Although this movement of receptors is remarkable, its role has been enigmatic. Recent developments have provided insight into the compartments through which the receptors move, the nature of the signals that trigger receptor translocation, and the significance of receptor cycling for cell function. In this article, Jennifer Koenig and Michael Edwardson review recent progress in this field and place receptor cycling into a mathematical framework that reveals the extent and rate of intracellular receptor movement.
 
Article
Anti-craving compounds have recently been registered for relapse prophylaxis in weaned alcoholics in various European countries (acamprosate), and in the United States (naltrexone). Acamprosate, the Ca(2+)-salt of N-acetyl-homotaurinate, interacts with NMDA receptor-mediated glutamatergic neurotransmission in various brain regions and reduces Ca2+ fluxes through voltage-operated channels. The opioid receptor antagonist naltrexone most likely interferes with alcohol-induced reinforcement via the block of opioid receptors. In this article Rainer Spanagel and Walter Zieglgänsberger discuss the pivotal role of incremental neuroadaptation to alcohol and alcohol-associated stimuli for craving, and the possible mechanisms of action underlying the anti-craving properties of acamprosate and naltrexone.
 
Article
The peripheral-type benzodiazepine receptor or recognition site (PBR) is a widely distributed transmembrane protein that is located mainly in the outer mitochondrial membrane. The PBR binds to high-affinity drug ligands and cholesterol. Many functions are associated directly or indirectly with the PBR, including the regulation of cholesterol transport and the synthesis of steroid hormones, porphyrin transport and heme synthesis, apoptosis, cell proliferation, anion transport, regulation of mitochondrial functions and immunomodulation. Based on these functions, there are many potential clinical applications of PBR modulation, such as in oncologic, endocrine, neuropsychiatric and neurodegenerative diseases. Although "PBR" is a widely used and accepted name in the scientific community, recent data regarding the structure and molecular function of this protein increasingly support renaming it to represent more accurately its subcellular role (or roles) and putative tissue-specific function (or functions). Translocator protein (18kDa) is proposed as a new name, regardless of the subcellular localization of the protein.
 
Article
Following the elucidation of the amino acid sequences of the mu-, delta- and kappa-opioid receptors, a new 'orphan opioid receptor' was cloned with a high degree of homology to the 'classical' opioid receptors. The endogenous opioid peptides show little or no activity at this new receptor; however, a novel endogenous peptide for the orphan opioid receptor has been isolated and sequenced. Here, Graeme Henderson and Sandy McKnight review recent findings on this new receptor and its endogenous ligand, and address the contentious issue of whether activation of this receptor results in hyperalgesia or analgesia.
 
Article
The proposal that endogenously produced carbon monoxide (CO) may act as a biological messenger has remained controversial. Carbon monoxide is generated by haem oxygenase isoenzymes in the degradation of haem-containing molecules. Certain metalloporphyrins, which are inhibitors of haem oxygenase, have been widely used as pharmacological tools in order to establish a messenger role for CO in the brain and periphery. However, increasing evidence shows that many metalloporphyrins are also associated with a large range of undesired effects, which make the interpretation of results using such compounds very uncertain. In this article, Lars Grundemar and Lars Ny evaluate the properties and describe the nonselective effect profile of such metalloporphyrins.
 
Article
There is now good reason to believe that blockade of the adenosine A2A receptor could be of value in the treatment of Parkinson's disease. Peter J. Richardson, Hiroshi Kase and Peter G. Jenner review the actions of this receptor in the striatum, emphasizing its ability to modulate the neuronal activity of striatal GABA-releasing output neurones, and showing that recently developed A2A receptor antagonists are capable of reducing the disabling effects of nigral cell degeneration in primates. They conclude that such antagonists may be useful as novel therapeutic agents for the treatment of Parkinson's disease.
 
Article
The GABAA receptor belongs, along with the nicotinic acetylcholine receptor, the glycine receptor and the 5-HT3 receptor, to a family of homologous transmitter-gated ion channels mediating fast synaptic transmission. Many classes of drug interact with the GABAA receptor, which is the major inhibitory ion channel in the mammalian brain. Among these drugs are the allosteric modulators acting at the benzodiazepine binding site. In this article, Erwin Sigel and Andreas Buhr discuss recent studies that have identified amino acid residues that are thought to form the binding pocket for these compounds. These residues are probably located at subunit interfaces of the protein pentamer and at least some of them are homologous to residues implicated in channel agonist binding. This implies pseudosymmetry of channel agonist and channel modulatory sites, which may be, as recent data indicate, a general principle realized in other pseudosymmetric protein complexes.
 
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The past ten years have provided an embarrassment of riches for those interested in cloned voltage-gated K+ (Kv) channels. Details of their physiology and pharmacology in expression systems, and their precise cellular location abound, making them excellent targets for pharmacologists. However, there is still a considerable and important gap in our knowledge between the behaviour of expressed Kv channels and K+ currents in vivo. In this review Brian Robertson focuses on a few of the recent developments in the field of Kv channels, namely modulation of their behaviour by accessory subunits, their control, and localization of identified Kv subunits.
 
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Receptor subtypes for purines have been identified in a variety of tissues, increasing interest in the roles of purine-mediated signalling in pathophysiological processes. Growing evidence supports the involvement of one of the purinoceptor subtypes, P2X3, in nociception. In this article, recent studies of purine-mediated nociception and visceral pain will be discussed. Furthermore, a novel hypothesis is proposed for purine-mediated mechanosensory transduction where ATP released during distension from epithelial cells lining tubes (such as ureter and gut) and sacs (such as the bladder) acts on P2X3 receptors on a subepithelial nerve plexus to initiate impulses that are relayed via the spinal cord to pain centres in the brain.
 
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Top-cited authors
John Garthwaite
  • University College London
Bertil B Fredholm
  • Karolinska Institutet
Terry P Kenakin
  • University of North Carolina at Chapel Hill
Geoffrey Burnstock
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Peter J Barnes
  • Imperial College London