Astroglial amino acid-based transmitter receptors

Amino acids appear in prebiotic period being one of the first organic molecules on Earth. For neurobiologists, it is of importance that AAs are not only representing building blocks of life, but are also the essential part of metabolism and cellular signaling. In the mammalian brain, the most common excitatory and inhibitory transmitters acting upon cellular plasmalemmal receptors are the amino acid glutamate and its derivative γ-aminobutyric acid, respectively. Other amino acids, i.e. aspartate, glycine, d-serine, and homocysteic acid, as well as the sulfonic acid taurine, are also active compounds involved in receptor-mediated brain signaling. Receptors for these amino acid-based transmitters are either ion channels, also referred to as ionotropic receptors, or metabotropic, i.e. seven transmembrane domain G-protein coupled receptors. In this mini-review, we focus our interest on amino acid-based transmitter receptors on neuroglia, astrocytes in particular.     

Autocrine signaling involved in cell volume regulation: the role of released transmitters and plasma membrane receptors

Cell volume regulation is a basic homeostatic mechanism transcendental for the normal physiology and function of cells. It is mediated principally by the activation of osmolyte transport pathways that result in net changes in solute concentration that counteract cell volume challenges in its constancy. This process has been described to be regulated by a complex assortment of intracellular signal transduction cascades. Recently, several studies have demonstrated that alterations in cell volume induce the release of a wide variety of transmitters including hormones, ATP and neurotransmitters, which have been proposed to act as extracellular signals that regulate the activation of cell volume regulatory mechanisms. In addition, changes in cell volume have also been reported to activate plasma membrane receptors (including tyrosine kinase receptors, G-protein coupled receptors and integrins) that have been demonstrated to participate in the regulatory process of cell volume. In this review, we summarize recent studies about the role of changes in cell volume in the regulation of transmitter release as well as in the activation of plasma membrane receptors and their further implications in the regulation of the signaling machinery that regulates the activation of osmolyte flux pathways. We propose that the autocrine regulation of Ca2+-dependent and tyrosine phosphorylation-dependent signaling pathways by the activation of plasma membrane receptors and swelling-induced transmitter release is necessary for the activation/regulation of osmolyte efflux pathways and cell volume recovery. Furthermore, we emphasize the importance of studying these extrinsic signals because of their significance in the understanding of the physiology of cell volume regulation and its role in cell biology in vivo, where the constraint of the extracellular space might enhance the autocrine or even paracrine signaling induced by these released transmitters.     

The coexistence of multiple receptors in a single nerve terminal provides evidence for pre-synaptic integration

Excitatory synaptic transmission is inhibited by G protein coupled receptors, including the adenosine A₁, GABA_B, and metabotropic glutamate receptor 7. These receptors are present in nerve terminals where they reduce the release of glutamate through activating signaling pathways negatively coupled to Ca²⁺ channels and adenylyl cyclase. However, it is not clear whether these receptors operate in distinct subpopulations of nerve terminals or if they are co-expressed in the same nerve terminals, despite the functional consequences that such distributions may have on synaptic transmission. Applying Ca²⁺ imaging and immunocytochemistry, we show that these three G protein coupled receptors coexist in a subpopulation of cerebrocortical nerve terminals. The three receptors share an intracellular signaling pathway through which their inhibitory responses are integrated and coactivation of these receptors produced an integrated response. Indeed, this response was highly variable, from a synergistic response at subthreshold agonist concentrations to an occluded response at high agonist concentrations. The presence of multiple receptors in a nerve terminal could be responsible for the physiological effects of neurotransmitter spillover from neighboring synapses or alternatively, the co-release of transmitters by the same nerve terminal.     

Beta-adrenergic axis and heart disease

Beta-adrenergic receptors (beta-ARs) belong to a large family of G-protein-coupled receptors (GPCRs) that form the interface between the sympathetic nervous system and the cardiovascular system. The beta-AR signal system is one of the most powerful regulators of cardiac function, mediated by the effects of the sympathetic transmitters epinephrine and norepinephrine. In a number of cardiac diseases, however, the biology of beta-AR signaling pathways is altered dramatically. Here we discuss the role of beta-AR signaling in the normal and abnormal heart and how the use of genetically engineered mouse models has helped in our understanding of the pathophysiology of cardiac disease.     

Taste buds as peripheral chemosensory processors

Taste buds are peripheral chemosensory organs situated in the oral cavity. Each taste bud consists of a community of 50–100 cells that interact synaptically during gustatory stimulation. At least three distinct cell types are found in mammalian taste buds – Type I cells, Receptor (Type II) cells, and Presynaptic (Type III) cells. Type I cells appear to be glial-like cells. Receptor cells express G protein-coupled taste receptors for sweet, bitter, or umami compounds. Presynaptic cells transduce acid stimuli (sour taste). Cells that sense salt (NaCl) taste have not yet been confidently identified in terms of these cell types. During gustatory stimulation, taste bud cells secrete synaptic, autocrine, and paracrine transmitters. These transmitters include ATP, acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE), and GABA. Glutamate is an efferent transmitter that stimulates Presynaptic cells to release 5-HT. This chapter discusses these transmitters, which cells release them, the postsynaptic targets for the transmitters, and how cell–cell communication shapes taste bud signaling via these transmitters.     

Epithelial cells and their neighbors. II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells

Surface sensory enteroendocrine cells are established mucosal taste cells that monitor luminal contents and provide an important link in transfer of information from gut epithelium to the central nervous system. Recent studies now show that these cells can also mediate efferent signaling from the brain to the gut. Centrally elicited stimulation of vagal and sympathetic pathways induces release of melatonin, which acts at MT2 receptors to increase mucosal electrolyte secretion. Psychological factors as well mucosal endocrine cell hyperplasia are implicated in functional intestinal disorders. Central nervous influence on the release of transmitters from gut endocrine cells offers an exciting area of future gastrointestinal research with a clinical relevance.     

抑郁症单胺类递质受体研究进展

目前认为,抑郁症的发病主要与单胺类递质有关,单胺类递质受体系统在抑郁症的发病及治疗过程中会发生明显变化,本文综述了5-羟色胺受体,肾上腺素受体和多巴胺受体在抑郁症发病机制中所起作用的研究进展。     

Function of GABAergic and glutamatergic neurons in the stomach

-Aminobutyric acid (GABA) and L-glutamic acid (L-Glu) are transmitters of GABAergic and glutamatergic neurons in the enteric interneurons, targeting excitatory or inhibitory GABA receptors or glutamate receptors that modulate gastric motility and mucosal function. GABAergic and glutamatergic neuron immunoreactivity have been found in cholinergic enteric neurons in the stomach. GABA and L-Glu may also subserve hormonal and paracrine signaling. Disruption in gastrointestinal function following perturbation of enteric GABA receptors and glutamate receptors presents potential new target sites for drug development.     

Receptor-Mediated Interaction Between the Sympathetic Nervous System and Immune System in Inflammation

The sympathetic nervous system plays a central role in establishing communication between the central nervous system and the immune system during inflammation. Inflammation activates the sympathetic nervous system, which causes release of the transmitters of the sympathetic nerv-ous system in the periphery. The transmitters of the sympathetic nervous system are the cate-cholamines noradrenaline and adrenaline and the purines ATP, adenosine, and inosine. Once these transmitters are released, they stimulate both presynaptic receptors on nerve terminals and post-synaptic receptors on immune cells. The receptors that are sensitive to catecholamines are termed adrenoceptors, whereas the receptors that bind purines are called purinoceptors. Stimulation of the presynaptic receptors exerts an autoregulatory effect on the release of transmitters. Ligation of the postsynaptic receptors on inflammatory cells modulates the inflammatory ac-tivities of these cells. The present review summarizes some of the most important aspects of the current state of knowledge about the interactions between the sympathetic nervous system and the immune system during inflammation with a special emphasis on the role of adreno and purinoceptors.     

Transmitters in early embryogenesis (new data)

New author's findings and published experimental data on participation of transmitters in first cleavage divisions are discussed. The data on qualitative peculiarities of intracellular transmitter receptors (or their functional equivalents), functional coupling of transmitters with secondary messengers and role of cortical cytoskeleton in realization of transmitter functions are confirmed.     

Homeostatic activity-dependent paradigm for neurotransmitter specification

Calcium-signaling plays a central role in specification of the chemical transmitters neurons express, adjusting the numbers of cells that express excitatory and inhibitory transmitters as if to achieve homeostatic regulation of excitability. Here we review the extent to which this activity-dependent regulation is observed for a range of different transmitters. Strikingly the homeostatic paradigm is observed both for classical and for peptide transmitters and in mature as well as in embryonic nervous systems. Transmitter homeostasis adds another dimension to homeostatic regulation of function in the nervous system that includes regulation of levels of voltage-gated ion channels, densities of neurotransmitter receptors, and synapse numbers and strength.     

High-resolution quantitative visualization of glutamate and GABA receptors at central synapses

Glutamate and GABA are the main transmitters in the central nervous system and their effects are mediated by ionotropic and metabotropic receptors. Immunogold electron microscopy has revealed the quantitative localization of these receptors at 20-30nm resolution. SDS-digested freeze-fracture replica labeling (SDS-FRL), a newly developed immunogold method, provides an accurate estimate of molecule numbers. Here, we summarize the recent advances in quantitative receptor localization, including use of SDS-FRL analyses to determine numbers of AMPA-type glutamate receptors in the cerebellum. The two-dimensional view and high sensitivity of SDS-FRL have revealed small, irregularly shaped AMPA receptor clusters within cerebellar synapses.     

New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram

The concepts of coexistence of transmitters and of receptor-receptor interactions have increased our understanding of the integrative processes regulating synaptic homeostasis and synaptic plasticity. Depending upon the ionotropic or metabotropic characteristics of the cotransmitter, it may be mainly involved in synaptic homeostasis or synaptic plasticity, respectively. A chemical trace of the postsynaptic activity can be obtained because of the plasticity of the receptor molecules. Thus, the heuristic hypothesis is introduced that islands of receptors located on postsynaptic membranes of local circuits can be formed by means of receptor-receptor interactions favouring ordered electrotonic sequences in the local circuits. This hypothesis has been named the receptor mosaic hypothesis of the engram. The islands or clusters of receptors can then store specific and complex information and when activated by the transmitters they may induce unique changes in ion permeability and cell metabolism which, at the local circuit level, can mimic exactly a previous electrotonic sequence. They can therefore represent at least part of the engram. This hypothesis is introduced against the background of the possible existence of different types of encodings of memory.     

P2X7-mediated ATP secretion is accompanied by depletion of cytosolic ATP

Purinergic Signalling - ATP and its metabolites are important extracellular signal transmitters acting on purinergic P2 and P1 receptors. Most cells can actively secrete ATP in response to a...     

Synaptic transmission in the pineal eye of young Xenopus laevis tadpoles: a role for NMDA and non-NMDA glutamate and non-glutaminergic receptors?

The pineal eye of Xenopus laevis tadpoles is directly photosensitive. A sudden reduction in light intensity produces a burst of activity in the pineal ganglion cells, which is closely followed by the onset of swimming. In this paper I present the results of experiments on the effects of agonists and antagonists of candidate pineal transmitters on ganglion cell activity. I found that NMDA and non-NMDA excitatory amino acid (EAA) agonists increased pineal activity, indicating the presence of both types of receptor. Kynurenic acid reduced activity, thus confirming that the photoreceptor transmitter is an EAA. Under physiological conditions, CNQX blocked activity almost completely whilst AP5 had little effect. In Mg²⁺-free saline CNQX had a considerably smaller effect, but joint application of CNQX and AP5 blocked almost all activity; therefore, the NMDA receptors are subject to blockage by Mg²⁺. Although GABA_A and ACh receptors appear to be present, no evidence was found for GABA or ACh as pineal transmitters. In addition, 5-HT had no effect on pineal activity. The main pineal transmitter is an EAA acting on ganglion cells through both NMDA and non-NMDA receptors. Other receptors are present but appear to have no role in controlling pineal activity at this stage. Accepted: 1 March 1997     

Dopamine receptor localization in the mammalian retina

After a short history of dopamine receptor discovery in the retina and a survey on dopamine receptor types and subtypes, the distribution of dopamine receptors in the retinal cells is described and correlated with their possible role in cell and retinal physiology. All the retinal cells probably bear dopamine receptors. For example, the recently discovered D_1B receptor has a possible role in modulating phagocytosis by the pigment epithelium and a D₄ receptor is likely to be involved in the inhibition of melatonin synthesis in photoreceptors. Dopamine uncouples horizontal and amacrine cell-gap junctions through D₁-like receptors. Dopamine modulates the release of other transmitters by subpopulations of amacrine cells, including that of dopamine through a D₂ autoreceptor. Ganglion cells express dopamine receptors, the role of which is still uncertain. Müller cells also are affected by dopamine. A puzzling action of dopamine is observed in the ciliary retina, in which D₁- and D₂-like receptors are likely to be involved in the cyclic regulation of intraocular pressure. Most of the dopaminergic actions appears to be extrasynaptic and the signaling pathways remain uncertain. Further studies are needed to better understand the multiple actions of dopamine in the retina, especially those that implicate rhythmic regulations.     

Paracrine intercellular communication by a Ca2+- and SNARE-independent release of GABA and glutamate prior to synapse formation

GABA and glutamate receptors are expressed in immature "silent" CA1 pyramidal neurons prior to synapse formation, but their function is unknown. We now report the presence of tonic, spontaneous, and evoked currents in embryonic and neonatal CA1 neurons mediated primarily by the activation of GABA(A) receptors. These currents are mediated by a nonconventional release of transmitters, as they persist in the presence of calcium channel blockers or botulinium toxin and are observed in Munc18-1-deficient mice in which vesicular release is abolished. This paracrine communication is modulated by glutamate but not GABA transporters, which do not operate during this period of life. Thus, a Ca(2+)- and SNARE-independent release of transmitters underlies a paracrine mode of communication before synapse formation.     

Amino acids as transmitters of synaptic excitation in neocortical sensory processes.

Few synaptic transmitters are known to exist that are not represented in some region or another, or at some layer or other, in the cerebral cortex of mammalian brain. The more difficult job than mere identification of which substances are present, is that of the assignment of particular functional role(s) of such substances, and as well, of determining upon exactly which element(s) of the known synaptic circuitry of neocortex, such transmitters operate. Current wisdom subscribes to the view that the excitatory amino acids, most likely L-glutamate, and L-aspartate but perhaps also L-cysteate, L-homocysteate, L-cysteine sulfinate or even (although much less likely) the endogenous dipeptide substance, N-acetyl-L-aspartyl-L-glutamate, are the major excitatory synaptic transmitters of intracortical (associational) fibres, of corticofugal projections, and, as this article will attest, of thalamocortical inputs, as well. What particular limits, or restrictions, are imposed upon these generalizations, such as whether the data pertain only to primary sensory areas or follow some other yet to be determined rule, remains to be discovered in future experiments. This paper first presents an overview of the advances in understanding that have come about during the past few decades concerning the synaptic roles of amino acid transmitters. Next, an experimental section presents new evidence based on release studies and the microiontophoretic approach, which supports the view that the amino acids, glutamate and aspartate, interact with specific, pharmacologically identified subtypes of receptors in neocortex as transmitters of synaptic excitation released from thalamic afferent terminals.