Major Classes Of Receptors Research Articles

Lysophospholipid receptors in neurodegeneration and neuroprotection.

The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson's disease, Huntington's disease, Rett syndrome, Alzheimer's disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.

Puncta-localized TRAF domain protein TC1b contributes to the autoimmunity of snc1.

Immune receptors play important roles in the perception of pathogens and initiation of immune responses in both plants and animals. Intracellular nucleotide-binding domain leucine-rich repeat (NLR)-type receptors constitute a major class of receptors in vascular plants. In the Arabidopsis thaliana mutant suppressor of npr1-1, constitutive 1 (snc1), a gain-of-function mutation in the NLR gene SNC1 leads to SNC1 overaccumulation and constitutive activation of defense responses. From a CRISPR/Cas9-based reverse genetics screen in the snc1 autoimmune background, we identified that mutations in TRAF CANDIDATE 1b (TC1b), a gene encoding a protein with four tumor necrosis factor receptor-associated factor (TRAF) domains, can suppress snc1 phenotypes. TC1b does not appear to be a general immune regulator as it is not required for defense mediated by other tested immune receptors. TC1b also does not physically associate with SNC1, affect SNC1 accumulation, or affect signaling of the downstream helper NLRs represented byACTIVATED DISEASE RESISTANCE PROTEIN 1-L2 (ADR1-L2), suggesting that TC1b impacts snc1 autoimmunity in a unique way. TC1b can form oligomers and localizes to punctate structures of unknown function. The puncta localization of TC1b strictly requires its coiled-coil (CC) domain, whereas the functionality of TC1b requires the four TRAF domains in addition to the CC. Overall, we uncovered the TRAF domain protein TC1b as a novel positive contributor to plant immunity.

A novel allele of the Arabidopsis thaliana MACPF protein CAD1 results in deregulated immune signaling.

Immune recognition in plants is governed by two major classes of receptors: pattern recognition receptors (PRRs) and nucleotide-binding leucine-rich repeat receptors (NLRs). Located at the cell surface, PRRs bind extracellular ligands originating from microbes (indicative of "non-self") or damaged plant cells (indicative of "infected-self"), and trigger signaling cascades to protect against infection. Located intracellularly, NLRs sense pathogen-induced physiological changes and trigger localized cell death and systemic resistance. Immune responses are under tight regulation in order to maintain homeostasis and promote plant health. In a forward-genetic screen to identify regulators of PRR-mediated immune signaling, we identified a novel allele of the membrane-attack complex and perforin (MACPF)-motif containing protein CONSTITUTIVE ACTIVE DEFENSE 1 (CAD1) resulting from a missense mutation in a conserved N-terminal cysteine. We show that cad1-5 mutants display deregulated immune signaling and symptoms of autoimmunity dependent on the lipase-like protein ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), suggesting that CAD1 integrity is monitored by the plant immune system. We further demonstrate that CAD1 localizes to both the cytosol and plasma membrane using confocal microscopy and subcellular fractionation. Our results offer new insights into immune homeostasis and provide tools to further decipher the intriguing role of MACPF proteins in plants.

Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure

Purine nucleotides transduce cell membrane receptor responses and modulate ion channel activity. This is accomplished through conformational change in the structure of nucleotides and cell membrane associated proteins. The aim of this study is to enhance our understanding of nucleotide dependence in regard to signal transduction events, drug action and pharmacological promiscuity. Nucleotides and ligand structures regulating Gα protein subunits, voltage- and ligand-gated ion channels are investigated for molecular similarity using a computational program. Results differentiate agonist and antagonist structures, identify molecular similarity within nucleotide and ligand structures and demonstrate the potential of ligands to regulate nucleotide conformational change. Relative molecular similarity within nucleotides and the ligands of the major receptor classes provides insight into mechanisms of receptor and ion channel regulation. The nucleotide template model has some merit as an initial screening tool in the study and comparison of drug and hormone structures.

Reliability of Urine Strip Test For Confirmation of Methadone Poisoning in Children

Introduction: Methadone is a drug with biologic effects similar to morphine which acts via interacting with major classes of receptors κand µ. It has a half-life of 25 to 50 hours. Ingestion of this substance causes serious symptoms such as bradycardia, apnea, decreased level of consciousness, and death. Rapid diagnosis and treatment is life-saving. The methadone urine test is an easy to perform test which could detect the substance rapidly. This study was conducted to determine the reliability of the positive methadone urine test in the first and second days of poisoning in children below the age of 13 who have been poisoned with it. Materials and Methods : A total of 50 children below 13 years of age were enrolled in the study from April 2013 to April 2014. They were referred to Loghman Hakim Hospital with a history of incidental methadone ingestion and clinical symptoms congruent with methadone poisoning such as apnea, drowsiness, decreased level of consciousness, and bradycardia and miosis. Methadone urine strip test was performed on the first and second days. Five parameters (age, gender, dose of ingested methadone, urine SG, and urine pH) were tested and recorded for each patient. Results: This test is an accruable test for the detection of methadone (P value<0.05). Findings suggested that as little as 2 mg of methadone administration could lead to a positive urine test. The highest frequency of positive test was observed when the test was given between 6 to 12 hours after methadone ingestion and the lowest frequency was obtained in the first 6 hours after poisoning. It is suggested that the test result can be false negative if it is carried out in less than 6 hours after methadone consumption. Conclusions: According to the results of this study, the methadone urine drug screen test has high accuracy for detection of methadone in the urine. In addition, if the initial test result is negative in the first 24 hours, we recommend that the test should be repeated 24 hours after the ingestion; thus, two negative results in the first 48 hours of ingestion can rule out methadone poisoning by a probability of 98.5%. Keywords: Poisoning; Urine Test; Methadone; Child.

Discoidin Domain Receptors: Potential Actors and Targets in Cancer.

The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

Abstract B02: Complex molecular-scale dynamics of HER2 receptor transport in live SKBR3 breast cancer cells revealed by nanoscale quantum dot imaging

Abstract The dynamic behavior of proteins in the spatial and temporal context of a cell is critical for dictating downstream signaling and subsequent cellular effects. Human epidermal growth factor receptor 2 (HER2) is a ligand-less receptor tyrosine kinase whose heterodimerization with other HER receptors (EGFR, HER3, HER4) activates potent downstream signaling to modulate cell proliferation and survival. HER2 represents a major therapeutic target as its overexpression is prevalent in a major subset of invasive breast cancers. Yet while current understanding of HER2 signaling entails a broad sequence of signaling events, the spatiotemporal dynamics of how these signaling mechanisms are executed remains undefined. Here, we describe the molecular-scale motions that underlie HER2 signaling behavior in live cells using a bright and photostable anti-HER2 quantum dot (QD) probe designed and validated to track the receptor for long durations with high spatiotemporal resolution. Methods: HER2 was detected using an anti-HER2 affibody that was fused to a fluorogen activating peptide (FAP) which bound with high affinity to a fluorogen (Malachite Green)-QD complex. HER2-QDs were imaged in live unstimulated and stimulated human SKBR3 breast cancer cells. Cells were serum-starved overnight and: 1) received no treatment during the course of imaging (unstimulated) or 2) were chronically treated with the HER3 and HER4 specific ligand, heregulin-beta1 (HRG) during the course of imaging (stimulated). HRG was administered globally across all cells or locally to a specific cellular region. Trajectory information was analyzed using custom single particle tracking MATLAB software to measure key biophysical parameters. Results: The anti-HER2-QD probe showed robust and increased signal-to-noise compared to conventional organic dyes. Validation was measured by sensitive quantitation of single probes in low and high HER2-expressing cell lines with background non-specific binding of less than five probes per cell. HER2 motions were complex and composed of a heterogeneous composite of diffusive, constrained, and stationary motions. These motions were observed in the trajectories of HER2 receptors traveling along cellular protrusions, cell body, and along protrusions between adjacent cells. HRG stimulation produced morphological changes (e.g. membrane ruffling, protrusion growth) as well as changes in HER2 dynamics. HRG-stimulated cells demonstrated an increase in HER2 mobility (as measured by diffusion constant), increased speed (as measured by instantaneous velocity), and wider exploratory area (as measured by maximum trajectory distance) than in unstimulated cells. Interestingly, increased receptor mobility did not correlate strongly with a wider exploratory area, and more mobile receptors showed more constrained motion. Conclusions: In contrast to the simple diffusive motions previously reported for members of major classes of receptors (e.g. GPCRs, tyrosine kinase receptors), our sensitive measurements of HER2 receptor motion demonstrate complex molecular dynamics in both unstimulated and stimulated cells. Ligand stimulation induces changes in cell morphology such as membrane ruffling and protrusion growth that accompany changes in HER2 mobility and range of motion. The diversity of receptor dynamics suggest a heterogeneous environment in which HER2 engages. Future experiments include understanding the dynamic interplay between HER2 with the cytoskeleton and downstream signaling with HER2-targetting therapies using real-time measurements of HER2 molecular motions. Citation Format: Wai Yan Lam, Yi Wang, Mark J. Olah, Keith A. Lidke, Marcel Bruchez, Joe Gray, Tania Q. Vu. Complex molecular-scale dynamics of HER2 receptor transport in live SKBR3 breast cancer cells revealed by nanoscale quantum dot imaging. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B02.

Extracellular matrix composition determines astrocyte responses to mechanical and inflammatory stimuli

Astrocytes perform critical homeostatic physiological functions in the central nervous system (CNS) and are robustly responsive to injury, inflammation, or infection. We hypothesized that the components of the extracellular matrix (ECM), which are known to vary during development and in response to disease, determine astrocytic responses to injury and inflammation. We examined the response of primary astrocyte cultures grown on different ECM proteins to a mechanical wound (i.e., scratch). ECM substrates selected were laminin (Ln), vitronectin (Vn), fibronectin (Fn) or Tenascin C (TnC). We found that regrowth of the scratch wound was ECM dependent: recovery was arrested on fibronectin (Fn), almost complete on either Vn, Ln, or TnC. To determine whether ECM responses were also influenced by inflammation, we treated ECM plated cultures with interleukin-1β (IL-1β). We found that IL-1β arrested astrocyte growth on Ln, accelerated astrocyte growth on Fn and had no significant effect on astrocyte growth on TnC or Vn. We also determined that blocking β1integrins, the major class of receptors for all ECM proteins tested, prevented the robust response of astrocytes exposed to TnC, Ln and Vn, and also inhibited the robust effect of IL-1β to stimulate astrocyte growth on Fn. In addition, we evaluated downstream targets of integrin signaling, specifically the mammalian target of rapamycin (mTOR), and determined that activation of this pathway contributed to the response of astrocytes grown on TnC, but not on Ln, Vn or Fn. These findings provide new insights into the role of ECM as a source of heterogeneity of glial responses that may have important implications for neuropathological sequelae.

New therapeutic strategies targeting D1-type dopamine receptors for neuropsychiatric disease.

The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson's disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.

Mu Opioids and Their Receptors: Evolution of a Concept

Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.

The Growing Promiscuity of G Protein Coupled Receptors

The Growing Promiscuity of G Protein Coupled Receptors

Measuring Opsonic Phagocytosis via Fcγ Receptors and Complement Receptors on Macrophages

Phagocytosis is a cellular process that plays crucial roles in the removal of dead or dying cells, tissue remodeling, and host defense against invading pathogens. Most eukaryotic cells are decorated with glycoproteins containing terminal sialic acids, whose negative charges tend to repel cells, making so-called "nonspecific" phagocytosis a relatively inefficient process. Professional phagocytes are so designated because they express two major classes of receptors on their surfaces that are primarily involved in phagocytosis. Paradoxically, these receptors do not recognize microbes directly, but rather endogenous proteins that become tethered to microbes and target them for destruction. These are the Fcγ receptors that bind to the Fc portion of IgG and the complement receptors (CRs), which bind primarily to cleavage products of the third component of complement, C3. This unit describes assays that are used to measure these two types of macrophage phagocytosis.

Altered levels of glutamatergic receptors and Na +/K + ATPase-α1 in the prefrontal cortex of subjects with schizophrenia

Evidence has accumulated over the past years that dysregulation of glutamatergic neurotransmission maybe implicated in the pathophysiology of schizophrenia. Glutamate acts on two major classes of receptors: ionotropic receptors, which are ligand-gated ion channels, and metabotropic receptors (mGluRs), coupled to heterotrimeric G-proteins. Although several pharmacological evidences point to abnormal glutamatergic transmission in schizophrenia, changes in the expression of glutamatergic receptors in the prefrontal cortex of patients with schizophrenia remains equivocal. In the present work, we have investigated glutamatergic neurotransmission in schizophrenia by assessing the expression in Brodmann Area 10 of mGluR5, the AMPA receptor subunits GluR1 and GluR2, and Na +/K + ATPase-α1, a potential modulator of glutamate uptake in the brain. Semiquantitative analysis of the expression of these proteins from postmortem brains revealed a particularly prominent reduction of GluR1 and GluR2 expression in patients with schizophrenia vs the control group. Conversely, we observed an up-regulation in the levels of Na +/K + ATPase-α1 expression. Finally, no change in the protein levels of mGluR5 was observed in schizophrenia. Our findings support and expand the hypothesis of glutamatergic dysfunction in prefrontal cortex in the pathophysiology of schizophrenia.

Cross-talk between endocytic clearance and secretion in macrophages

Macrophages are essential elements of innate immunity that control inflammatory reactions, healing processes, tissue homeostasis and immune tolerance by the co-ordinated release and clearance of soluble mediators. Scavenger receptors (SRs) constitute a major class of receptors, which direct endocytosed material for degradation. SR-mediated uptake can result in both pro-inflammatory and tolerogenic programming of macrophages. While effects of SRs on the level of signal transduction are well documented, the effect of endocytosis on the regulated secretion, in particular lysosomal secretion, in macrophages remains to be elusive. Stabilin-1, SR identified and functionally characterized by us, mediates clearance of acLDL and universal regulator of tissue turn-over – SPARC. Unexpectedly for SRs, stabilin-1 shuttles between endosomal compartment and biosynthetic compartment and transports newly synthesized stabilin-interacting chitinase-like protein (SI-CLP) to the lysosomal secretory pathway. This sorting function of stabilin-1 is mediated by GGAs, clathrin adaptors responsible for the mannose-6-phosphate receptors (MPR)-mediated transport of lysosomal hydrolases. Moreover, stabilin-1 internalizes hormone placental lactogen, transports it to the trans-Golgi network-associated transcytosis. Thus stabilin-1 is the only known SR that links endocytic clearance, intracellular sorting and trancytosis. We propose novel level of regulation for the secretory repertoire of macrophages: cross-talk of uptake and release at the level of vesicular trafficking.

Structural modification of the highly potent peptide bradykinin B1 receptor antagonist B9958

Bradykinin (BK)-related peptides stimulate two major classes of receptors, B1 and B2. The B1 receptor (B1R) plays an important role in various pathophysiological states including chronic inflammation, pain, hypotension, trauma and proliferation of cancer. Therefore, there is interest in the development of highly potent peptide BK B1R antagonists. We previously developed a highly potent and selective BK B1R receptor antagonist, B9958 (Lys-Lys-[Hyp3, CpG5, d-Tic7, CpG8]des-Arg9-BK) (Hyp, trans-4-hydroxyproline; CpG, α-cyclopentylglycine; Tic, tetrahydroisoquinoline-3-carboxylic acid). We now report on new BK B1R antagonist analogs of B9958 with N-terminal basic residues in the d-configuration, or Lys-, Orn- derivatives (NiK, ε-nicotinoyllysine; PzO, 3-pyrazinoylornithine) and/or having hindered unusual amino acids at position 5 (Igl, α-(2-indanyl)glycine). These changes were designed to prevent enzyme degradation while keeping an acceptable affinity. However, these new analogs do not show higher B1R antagonist activity than B9958, but its N-terminal acylated derivative with a bulky and hydrophobic 2,3,4,5,6-pentafluorocinnamic acid (F5c), B10324, retains a B1R antagonist activity close to that of B9958 and, in addition, has high inhibition in vivo against lung cancer (SCLC, 86 %) and moderate inhibition against prostate cancer (PC3, 43%) xenografts. This class of compounds offers hope for the development of new BK antagonist peptide drugs for lung or prostate cancer.

Role of Receptors in Bacillus thuringiensis Crystal Toxin Activity

Bacillus thuringiensis produces crystalline protein inclusions with insecticidal or nematocidal properties. These crystal (Cry) proteins determine a particular strain's toxicity profile. Transgenic crops expressing one or more recombinant Cry toxins have become agriculturally important. Individual Cry toxins are usually toxic to only a few species within an order, and receptors on midgut epithelial cells have been shown to be critical determinants of Cry specificity. The best characterized of these receptors have been identified for lepidopterans, and two major receptor classes have emerged: the aminopeptidase N (APN) receptors and the cadherin-like receptors. Currently, 38 different APNs have been reported for 12 different lepidopterans. Each APN belongs to one of five groups that have unique structural features and Cry-binding properties. While 17 different APNs have been reported to bind to Cry toxins, only 2 have been shown to mediate toxin susceptibly in vivo. In contrast, several cadherin-like proteins bind to Cry toxins and confer toxin susceptibility in vitro, and disruption of the cadherin gene has been associated with toxin resistance. Nonetheless, only a small subset of the lepidopteran-specific Cry toxins has been shown to interact with cadherin-like proteins. This review analyzes the interactions between Cry toxins and their receptors, focusing on the identification and validation of receptors, the molecular basis for receptor recognition, the role of the receptor in resistant insects, and proposed models to explain the sequence of events at the cell surface by which receptor binding leads to cell death.

The Endogenous Opioid System and Clinical Pain Management

The endogenous opioid system is one of the most studied innate pain-relieving systems. This system consists of widely scattered neurons that produce three opioids: beta-endorphin, the met- and leu-enkephalins, and the dynorphins. These opioids act as neurotransmitters and neuromodulators at three major classes of receptors, termed mu, delta, and kappa, and produce analgesia. Like their endogenous counterparts, the opioid drugs, or opiates, act at these same receptors to produce both analgesia and undesirable side effects. This article examines some of the recent findings about the opioid system, including interactions with other neurotransmitters, the location and existence of receptor subtypes, and how this information drives the search for better analgesics. We also consider how an understanding of the opioid system affects clinical responses to opiate administration and what the future may hold for improved pain relief. The goal of this article is to assist clinicians to develop pharmacological interventions that better meet their patient's analgesic needs.

Opioid-somatostatin interactions in regulating cancer cell growth

Opioids and somatostatin mediate their cellular effects through specific membrane receptors. Three major receptor classes (delta, mu and kappa) were identified for opioids, while for somatostatin, five different receptor classes (SSTR1-5) have been cloned. Through the interaction with their receptors, opioids and somatostatin exert their effects on cell growth, proliferation, differentiation and secretion. Specific actions of each receptor type have been reported, to be implicated in one or more of the cell functions referred above but have been mainly correlated with cell growth control. In several systems the effect of either neuropeptide is the reverse, inducing cell growth rather than antiproliferative and proapoptotic signals. In recent years, a growing number of reports indicate a possible interaction between opioid and somatostatin system. This could occur at the receptor level, through a cross-interaction of either neuropeptide with either receptor type, or receptor hetero-dimerization, and at a post-receptor level, via interaction with specific signaling molecules. These interactions provide new directions for the identification of specific molecules acting at the receptor and post-receptor level, mimicking the effects of both categories of agents.

The synaptic linkage for tactile and kinaesthetic inputs to the dorsal column nuclei.

Our sensory abilities in touch and kinaesthesia depend upon approximately eight major classes of receptors and sensory nerve fibres. When individual fibres of these different kinaesthetic and tactile fibre classes are selectively activated in conscious human subjects by means of the intraneural microstimulation procedure there are quite marked differences observed among the classes in their capacity to generate perceptual responses. These differences may be attributable to differential transmission characteristics for different fibre classes at synaptic junctions within the sensory pathways. To test this hypothesis we have employed a paired, simultaneous recording paradigm in which we have examined the efficacy of transmission across the dorsal column nuclei (DCN) in a one-to-one synaptic linkage between single, identified tactile or kinaesthetic afferent fibres and their central DCN target neurons. These studies demonstrate a remarkable security of transmission for all fibre classes examined. For all classes, the minimum sensory input, a single impulse in one sensory fibre, can generate spike output from DCN target neurons. The results demonstrate that the differential capacities of various tactile and kinaesthetic fibre classes to generate perceptual responses when activated singly, do not appear to be explicable in terms of systematic differences in DCN transmission characteristics.

Telling tails.

The N-methyl-d-aspartate (NMDA)-type glutamate receptor is one of three major classes of receptors for glutamate, the principle excitatory neurotransmitter in the central nervous system. It plays a key role in learning and in the formation of memories by acting as a “coincidence detector” that initiates changes in synaptic strength that lead to the formation of new neural networks (1). It is also an important mediator of several forms of pathological neuronal toxicity. The NMDA receptor responds at a synapse only when the presynaptic terminal releases glutamate at the same time that the postsynaptic neuron is strongly depolarized by the sum of activating influences impinging on it. In effect, it initiates the strengthening of all synapses that depolarize the same postsynaptic neuron at the same time and thus triggers formation of a new, more stable circuit. When the NMDA-receptor channel opens, it allows passage of calcium ions, as well as sodium and potassium, into the cell. The calcium ions trigger a cascade of biochemical signaling reactions catalyzed by enzymes located just underneath the postsynaptic membrane. These reactions modify other membrane channels in the synapse, ultimately leading to a change in the strength of the electrical signal produced when the synapse is activated again.