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Metabotropic Receptors (metabotropic + receptor)
Selected AbstractsComparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: Immunohistochemical colocalization of the ,1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunitsTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 4 2004Henry J. Waldvogel Abstract The GABAB receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABABR1 and GABABR2. In this study, the cellular distribution of the GABABR1 and GABABR2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABAB receptor subunits GABABR1 and GABABR2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABABR1 and GABABR2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABAA ,1 subunit and GABAB receptor subunits showed that the GABAA receptor ,1 subunit and the GABABR1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABABR1 and GABABR2 were found on substantia nigra pars compacta neurons but the GABAA receptor ,1 subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABAA and GABAB receptors. That is, GABA acts through GABAB receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABAA receptors containing the ,1 subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata. J. Comp. Neurol. 470:339,356, 2004. © 2004 Wiley-Liss, Inc. [source] Differential loss and preservation of glutamate receptor function in bipolar cells in the rd10 mouse model of retinitis pigmentosaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2009Theresa Puthussery Abstract Photoreceptor degenerations can trigger morphological alterations in second-order neurons, however, the functional implications of such changes are not well known. We conducted a longitudinal study, using whole-cell patch-clamp, immunohistochemistry and electron microscopy to correlate physiological with anatomical changes in bipolar cells of the rd10 mouse , a model of autosomal recessive retinitis pigmentosa. Rod bipolar cells (RBCs) showed progressive changes in mGluR6-induced currents with advancing rod photoreceptor degeneration. Significant changes in response amplitude and kinetics were observed as early as postnatal day (P)20, and by P45 the response amplitudes were reduced by 91%, and then remained relatively stable until 6 months. These functional changes correlated with the loss of rod photoreceptors and mGluR6 receptor expression. Moreover, we showed that RBCs make transient ectopic connections with cones during progression of the disease. At P45, ON-cone bipolar cells (ON-CBCs) retain mGluR6 responses for longer periods than the RBCs, but by about 6 months these cells also strongly downregulate mGluR6 expression. We propose that the relative longevity of mGluR6 responses in CBCs is due to the slower loss of the cones. In contrast, ionotropic glutamate receptor expression and function in OFF-CBCs remains normal at 6 months despite the loss of synaptic input from cones. Thus, glutamate receptor expression is differentially regulated in bipolar cells, with the metabotropic receptors being absolutely dependent on synaptic input. These findings define the temporal window over which bipolar cells may be receptive to photoreceptor repair or replacement. [source] Chronic interleukin-6 alters the level of synaptic proteins in hippocampus in culture and in vivoEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Elly J. F. Vereyken Abstract There is now considerable evidence that the level of expression of the proinflammatory cytokine, interleukin-6 (IL-6), is increased in the central nervous system (CNS) during neuroinflammatory conditions such as occurs in neurological disorders and in disease and injury. However, our understanding of the consequences of increased expression of IL-6 on the CNS is still limited, especially with respect to the developing nervous system, which is known to be particularly vulnerable to environmental factors. To address this issue, we investigated the properties of cultured hippocampal neurons exposed chronically to IL-6 during the main period of morphological and physiological development, which occurs during the first 2 weeks of culture. IL-6 was tested at 500 U/mL, considered to reflect a pathophysiologic concentration. The morphological features of neuronal development in the control and IL-6-treated cultures appeared similar. However, Western blot analysis showed a significant reduction in the level of Group-II metabotropic receptors (mGluR2/3) and L-type Ca2+ channels in the IL-6-treated cultures. A similar reduction in mGluR2/3 and L-type Ca2+ channel protein was observed in transgenic mice that over-express IL-6 in the CNS through astrocyte production starting early in development. Analysis of Ca2+ signals produced by spontaneous synaptic network activity in the hippocampal cultures and effects of a mGluR2/3 agonist and antagonist showed that the reduced levels of mGluR2/3 impact on the functional properties of hippocampal synaptic network activity. These results have important implications relative to the mechanisms responsible for altered CNS function during conditions associated with increased levels of IL-6 in the CNS. [source] Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortexEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Masatoshi Suzuki Abstract Excitatory amino acids such as glutamate play important roles in the central nervous system. We previously demonstrated that a neurosteroid, dehydroepiandrosterone (DHEA), has powerful effects on the cell proliferation of human neural progenitor cells (hNPC) derived from the fetal cortex, and this effect is modulated through NMDA receptor signaling. Here, we show that glutamate can significantly increase the proliferation rates of hNPC. The increased proliferation could be blocked by specific NMDA receptor antagonists, but not other glutamate antagonists for kainate,AMPA or metabotropic receptors. The NR1 subunit of the NMDA receptor was detectable in elongated bipolar or unipolar cells with small cell bodies. These NR1-positive cells were colocalized with GFAP immunoreactivity. Detection of the phosphorylation of cAMP response element-binding protein (pCREB) revealed that a subset of NR1-positive hNPC could respond to glutamate. Furthermore, we hypothesized that glutamate treatment may affect mainly the hNPC with a radial morphology and found that glutamate as well as DHEA selectively affected elongated hNPC; these elongated cells may be a type of radial glial cell. Finally we asked whether the glutamate-responsive hNPC had an increased potential for neurogenesis and found that glutamate-treated hNPC produced significantly more neurons following differentiation. Together these data suggest that glutamate stimulates the division of human progenitor cells with neurogenic potential. [source] Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptorsEXPERIMENTAL PHYSIOLOGY, Issue 6 2010Colin A. Nurse The control of breathing depends critically on sensory inputs to the central pattern generator of the brainstem, arising from peripheral arterial chemoreceptors located principally in the carotid bodies (CBs). The CB receptors, i.e. glomus or type I cells, are excited by chemical stimuli in arterial blood, particularly hypoxia, hypercapnia, acidosis and low glucose, which initiate corrective reflex cardiorespiratory and cardiovascular adjustments. Type I cells occur in clusters and are innervated by petrosal afferent fibres. Synaptic specializations (both chemical and electrical) occur between type I cells and petrosal terminals, and between neighbouring type I cells. This, together with the presence of a wide array of neurotransmitters and neuromodulators linked to both ionotropic and metabotropic receptors, allows for a complex modulation of CB sensory output. Studies in several laboratories over the last ,20 years have provided much insight into the transduction mechanisms. More recent studies, aided by the development of a co-culture model of the rat CB, have shed light on the role of neurotransmitters and neuromodulators in shaping the afferent response. This review highlights some of these developments, which have contributed to our current understanding of information processing at CB chemoreceptors. [source] Astrocytic calcium signals induced by neuromodulators via functional metabotropic receptors in the ventral respiratory group of neonatal miceGLIA, Issue 8 2009Kai Härtel Abstract A controlled, periodic exchange of air between lungs and atmosphere requires a neuronal rhythm generated by a network of neurons in the ventral respiratory group (VRG) of the brainstem. Glial cells, e.g. astrocytes, have been shown to be supportive in stabilizing this neuronal activity in the central nervous system during development. In addition, a variety of neuromodulators including serotonin (5-HT), Substance P (SP), and thyrotropin-releasing hormone (TRH) stimulate respiratory neurons directly. If astrocytes in the VRG, like their neuronal neighbors, are also directly stimulated by neuromodulators, they might indirectly affect the respiratory neurons and consequently the respiratory rhythm. In the present study, we provide support for this concept by demonstrating expression of NK1-R, TRH-R, and 5-HT2 -R in astrocytes of the VRG with immunohistochemistry. Additionally, we showed that the external application of the neuromodulators 5-HT, SP, and TRH activate calcium transients in VRG astrocytes. Consequently, we postulate that in the VRG of the neonatal mouse, neuromodulation by SP, TRH, and serotonin also involves astrocytic calcium signaling. © 2008 Wiley-Liss, Inc. [source] Characterization of a novel G-protein coupled receptor from the parasitic nematode H. contortus with high affinity for serotoninJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Martin W. Smith The neurotransmitter serotonin (5HT) has been shown to modulate mobility, feeding, egg-laying, and defecation behaviors in the saprophytic nematode Caenorhabditis elegans. Although the effects of serotonin on these behaviors in parasitic nematodes is under study, little is known about the diversity, ontogeny, signaling, and pharmacology of serotonin receptors in these organisms. In an effort to increase our understanding of this system, we cloned and characterized a novel cDNA (5HT1Hc) from the parasitic nematode Haemonchus contortus that has high amino acid sequence homology with known G-protein coupled 5HT1-receptors from invertebrates and vertebrates. Transcript expression studies in four development stages (egg, L1/L2, L3, and adult) revealed the presence of the mRNA in the L1/L2, L3, and adult stages. Membranes from insect cells (Sf9) expressing the 5HT1Hc -receptor cDNA displayed nanomolar binding affinity to serotonin and a unique pharmacological profile distinct from known invertebrate and mammalian 5HT-receptors. Receptor signaling studies with mammalian AV12 cells expressing the 5HT1Hc -receptor and the promiscuous G-protein, G,15, demonstrated dose-dependent intracellular signals with serotonin acting as an agonist. Together, these studies describe a novel invertebrate 5HT-receptor with high affinity for the indolealkylamine, serotonin, and pharmacological properties that do not conform to any known members of this superfamily of metabotropic receptors. [source] Poster Sessions CP07: Ions, Channels, Pumps and TransportersJOURNAL OF NEUROCHEMISTRY, Issue 2002A. A. Boldyrev Stationary level of reactive oxygen species (ROS) in cerebellum granule cells of 12-day-old-rats was measured using three fluorescent dyes characteristic of different location within the neuronal cell: BODIPY 581/591 (for LOO.radicals), DCF-DA (for H202) and DHR123 (OH-radicals in mitochondria). When the neurons were activated by N-methyl- d -aspartate (NMDA) a dose- and time-dependent rise of the fluorescent signal was registered with each of the three dyes; the former dye provided the smallest and the latter the largest response. 3-HPG, a ligand for metabotropic receptors decreases ROS fluorescence and suppressed the NMDA-induced effect. NMDA and kainic acid presented simultaneously cumulatively increased ROS levels. Ouabain, specific inhibitors of Na/K-pump induced a considerable increase in ROS fluorescence, which was decreased by 2.5,5 mm KCl, 50 mkM Vanadate or 10 mkM D-AP5, an inhibitor of NMDA-activated ionic channels. The K0.5 for activation of ROS generation by Ouabain was more than 250 mkM, which is much higher than that for inhibition of Na/K-ATPase or its rubidium pumping activity. The data show that the Na/K-pump protein regulates ROS production by NMDA-receptors and that the E1(Na) conformation of the Na/K-pump being less sensitive to ouabain may be responsible for the effects. The data illustrate functional interaction between ionotropic and metabotropic receptors and Na/K-ATPase. Acknowledgements:, Supported by DAAD, Grant 325-sm, Germany. [source] Glutamate activation of Oct-2 in cultured chick Bergmann glia cells: Involvement of NF,BJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005J. Alfredo Méndez Abstract Glutamate, the major excitatory neurotransmitter in the central nervous system, is critically involved in gene expression regulation at the transcriptional and translational levels. Its activity through ionotropic as well as metabotropic receptors modifies the protein repertoire in neurons and glial cells. In avian cerebellar Bergmann glia cells, glutamate receptors trigger a diverse array of signaling cascades that include activity-dependent transcription factors such as the activator protein-1, the cAMP response-element binding protein, and Oct-2. We analyze the upstream regulatory elements involved in Oct-2 activation. Our results demonstrate that Ca2+ influx, protein kinase C, phosphatidylinositol-3 kinase, Src, and nuclear factor (NF),B are involved in this signaling pathway. Our findings link ,-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation to a negative phase of chkbp gene regulation, controlled by NF,B. © 2005 Wiley-Liss, Inc. [source] Presynaptic modulation of sensory neurons in the segmental ganglia of arthropodsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 4 2002Alan Hugh David WatsonArticle first published online: 3 SEP 200 Abstract The afferent terminals of arthropod sensory neurones receive abundant input synapses, usually closely intermingled with the sites of synaptic output. The majority of the input synapses use the neurotransmitter GABA, but in some afferents there is a significant glutamatergic or histaminergic component. GABA and histamine shunt afferent action potentials by increasing chloride conductance. Though glutamate can also have this effect in the arthropod central nervous system, its action on afferent terminals appears to be mediated by increases in potassium conductance or by the action of metabotropic receptors. The action of the presynaptic synapses on the afferents are many and varied. Even on the same afferent, they may have several distinct roles that can involve both tonic and phasic patterns of primary afferent depolarisation. Despite the ubiquity and importance of their effects however, the populations of neurones from which the presynaptic synapses are made, remain largely unidentified. Microsc. Res. Tech. 58:262,271, 2002. © 2002 Wiley-Liss, Inc. [source] Replacing the rod with the cone transducin , subunit decreases sensitivity and accelerates response decayTHE JOURNAL OF PHYSIOLOGY, Issue 17 2010C.-K. Chen Cone vision is less sensitive than rod vision. Much of this difference can be attributed to the photoreceptors themselves, but the reason why the cones are less sensitive is still unknown. Recent recordings indicate that one important factor may be a difference in the rate of activation of cone transduction; that is, the rising phase of the cone response per bleached rhodopsin molecule (Rh*) has a smaller slope than the rising phase of the rod response per Rh*, perhaps because some step between Rh* and activation of the phosphodiesterase 6 (PDE6) effector molecule occurs with less gain. Since rods and cones have different G-protein , subunits, and since this subunit (T,) plays a key role both in the interaction of G-protein with Rh* and the activation of PDE6, we investigated the mechanism of the amplification difference by expressing cone T, in rod T,-knockout rods to produce so-called GNAT2C mice. We show that rods in GNAT2C mice have decreased sensitivity and a rate of activation half that of wild-type (WT) mouse rods. Furthermore, GNAT2C responses recover more rapidly than WT responses with kinetic parameters resembling those of native mouse cones. Our results show for the first time that part of the difference in sensitivity and response kinetics between rods and cones may be the result of a difference in the G-protein , subunit. They also indicate more generally that the molecular nature of G-protein , may play an important role in the kinetics of G-protein cascades for metabotropic receptors throughout the body. [source] The contribution of intracellular calcium stores to mEPSCs recorded in layer II neurones of rat barrel cortexTHE JOURNAL OF PHYSIOLOGY, Issue 2 2002Christopher R. L. Simkus Loading slices of rat barrel cortex with 50 ,m BAPTA-AM while recording from pyramidal cells in layer II induces a marked reduction in both the frequency and amplitudes of mEPSCs. These changes are due to a presynaptic action. Blocking the refilling of Ca2+ stores with 20 ,m cyclopiazonic acid (CPA), a SERCA pump inhibitor, in conjunction with neuronal depolarisation to activate Ca2+ stores, results in a similar reduction of mEPSCs to that observed with BAPTA-AM, indicating that the source for intracellular Ca2+ is the endoplasmic reticulum. Block or activation of ryanodine receptors by 20 ,m ryanodine or 10 mm caffeine, respectively, shows that a significant proportion of mEPSCs are caused by Ca2+ release from ryanodine stores. Blocking IP3 receptors with 14 ,m 2-aminoethoxydiphenylborane (2APB) also reduces the frequency and amplitude of mEPSCs, indicating the involvement of IP3 stores in the generation of mEPSCs. Activation of group I metabotropic receptors with 20 ,m (RS) -3,5-dihydroxyphenylglycine (DHPG) results in a significant increase in the frequency of mEPSCs, further supporting the role of IP3 receptors and indicating a role of group I metabotropic receptors in causing transmitter release. Statistical evidence is presented for Ca2+ -induced Ca2+ release (CICR) from ryanodine stores after the spontaneous opening of IP3 stores. [source] Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) and demethyl-ACPA,CHIRALITY, Issue 9 2001Tommy N. Johansen Abstract We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC columns. Furthermore, the enantiopharmacology of ACPA and demethyl-ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)-ACPA showed high affinity in AMPA binding (IC50 = 0.025 ,M), low affinity in kainic acid binding (IC50 = 3.6 ,M), and potent AMPA receptor agonist activity on cortical neurons (EC50 = 0.25 ,M), whereas (R)-ACPA was essentially inactive. Like (S)-ACPA, (S)-demethyl-ACPA displayed high AMPA receptor affinity (IC50 = 0.039 ,M), but was found to be a relatively weak AMPA receptor agonist (EC50 = 12 ,M). The stereoselectivity observed for demethyl-ACPA was high when based on AMPA receptor affinity (eudismic ratio = 250), but low when based on electrophysiological activity (eudismic ratio = 10). (R)-Demethyl-ACPA also possessed a weak NMDA receptor antagonist activity (IC50 = 220 ,M). Among the enantiomers tested, only (S)-demethyl-ACPA showed activity at metabotropic receptors, being a weak antagonist at the mGlu2 receptor subtype (KB = 148 ,M). Chirality 13:523,532, 2001. © 2001 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||