Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CNS function depends on a capacity for plasticity during development, following injury, and in response to changing environmental conditions. Functional alterations in signal transduction pathways and in neurotransmitter receptor expression are possible mechanisms for the expression of such plasticity. In the present report, we demonstrate that exposure of astrocytes to specific growth factors alters both the functional activity and the protein levels of a specific glutamate receptor. Exposure of astrocytes to basic fibroblast growth factor, epidermal growth factor, or transforming growth factor-alpha produced marked increases in the ability of metabotropic glutamate receptor (mGluR) agonists to stimulate phosphoinositide hydrolysis. Using Western immunoblotting, we demonstrate that an increase in the levels of one of the phosphoinositide-coupled mGluR subtypes, mGluR5, accompanies the increased ability of mGluR agonists to stimulate phosphoinositide hydrolysis. In contrast, another phosphoinositide-coupled subtype of this receptor family, mGluR1 alpha, was not present at detectable levels in these cultures. The enhanced stimulation of phosphoinositide hydrolysis showed little sensitivity to pertussis toxin, and appeared to be selective to mGluR agonists, as there was not a similar increase in the ability of norepinephrine or carbachol to stimulate phosphoinositide hydrolysis. These findings demonstrate that expression of mGluRs in astrocytes is plastic, and indicate a novel pathway through which specific growth factors may selectively modulate neurotransmitter action.
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PMID:Growth factor upregulation of a phosphoinositide-coupled metabotropic glutamate receptor in cortical astrocytes. 766 94

G-protein-coupled receptor (GPCR) agonist-activated transformation of NIH/3T3 fibroblast cells has been documented by many workers. Our present interest is in the growth control exerted by these agonists. The mechanisms involved in GPCR agonist-activated growth regulation are not known and investigations using existing cell lines are complicated by the endogenous expression of numerous different GPCRs as well as by the fact that these cell lines are cultured in serum that contains naturally occurring agonists for these receptors. To study the agonist induced growth response of cells transfected with either delta-opioid or serotonin-5HT2C neurotransmitter receptor genes, we have developed new clonal cell lines derived from NIH/3T3 mouse fibroblast cells. These new cell lines, designated with the suffix 3T3DA, can be cultured stably in serum-free, hormone-defined medium: insulin is the only exogenous growth factor added to the culture medium of proliferating 3T3DA cell lines, and their proliferation can be stopped and started by the respective removal or addition of insulin. Micromolar concentrations of agonists were used to activate the corresponding opioid and serotonin receptors over periods extending to 6 days. We observed distinct patterns of GPCR-specific, agonist-activated growth regulation in serum-free cultures, but not in serum-supplemented cultures. At concentrations > 10 microM, morphine inhibits growth of delta-opioid receptor-expressing cells by 40% with respect to normal 3T3DA cells. Opioid agonist induced inhibition of cyclic AMP (cAMP) production as well as growth down-regulation are pertussis toxin sensitive indicating that the exogenously expressed delta-opioid receptors demonstrate classical opioid receptor signaling. The presence of 1 microM serotonin stimulates growth of serotonin-5HT2C receptor- expressing cells by approximately 100% with respect to normal 3T3DA cells. Neither the untreated nor the agonist-treated cells form colonies in soft agar, indicating that they retain anchorage-dependent growth control. These cell lines provide a simple system that could be used as a tool for probing the complex molecular mechanisms associated with GPCR agonist-activated growth control.
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PMID:Hormone-defined cell system for studying G-protein coupled receptor agonist-activated growth modulation: delta-opioid and serotonin-5HT2C receptor activation show opposite mitogenic effects. 911 93

The effect of a novel cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) on cAMP formation was investigated in both slices and membranes of the rat cerebral cortex. NS-105 (10(-8)-10(-6) M) inhibited forskolin-stimulated cAMP formation in membranes, however, the compound significantly enhanced the cAMP formation in pertussis toxin-pre-treated membranes, an action that was abolished by cholera toxin. In contrast, in digitonin-permeabilized membranes, NS-105 had no influence on Mn2+-stimulated cAMP formation. Both of the inhibitory and facilitatory actions of NS-105 on cAMP formation were mimicked by a metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and an adrenergic alpha2 agonist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonopropanoate but not by an alpha2 antagonist yohimbine. In cortical slices, NS-105 (10(-8)-10(-7) M) inhibited forskolin-stimulated cAMP accumulation but enhanced isoproterenol-stimulated cAMP accumulation, as did by a GABA(B) agonist (-)baclofen. On the other hand, (-)baclofen, while it significantly inhibited cAMP accumulation in slices, did no longer inhibit cAMP accumulation, when treated with NS-105 (10(-8)-10(-5) M). Similarly, (-)baclofen-induced inhibition of the cAMP accumulation was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10(-6)) increased [35S]GTPgammaS binding in the intact but not digitonin-permeabilized cortical membranes, as produced by UK-14,304, although the compound (10(-9)-10(-3) M) had no influence on various neurotransmitter receptor bindings, including alpha2 receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs which might coupled to both Gi/Go and Gs.
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PMID:Involvement of metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate cyclase activity induced by a novel cognition enhancer NS-105 in rat brain. 913 67

The inhibition of presynaptic calcium channels via G-protein-dependent second messenger pathways is a key mechanism of transmitter release modulation. We used the calyx-type nerve terminal of the chick ciliary ganglion to examine which G-proteins are involved in the voltage-sensitive inhibition of presynaptic N-type calcium channels. Adenosine caused a prominent inhibition of the calcium current that was totally blocked by pretreatment with pertussis toxin (PTX), consistent with an exclusive involvement of G(o)/G(i) in the G-protein pathway. Immunocytochemistry was used to localize these G-protein types to the nerve terminal and its transmitter release face. We used two approaches to test for modulation by other G-protein types. First, we treated the terminals with ligands for a variety of G-protein-linked neurotransmitter receptor types that have been associated with different G-protein families. Although small inhibitory effects were observed, these could all be eliminated by PTX, indicating that in this terminal the G(i) family is the sole transmitter-induced G-protein inhibitory pathway. Second, we examined the kinetics of calcium channel inhibition by uncaging the nonselective and irreversible G-protein activator GTPgammaS, bypassing the receptors. A large fraction of the rapid GTPgammaS-induced inhibition persisted, consistent with a G(o)/G(i)-independent pathway. Immunocytochemistry identified G(q), G(11), G(12), and G(13) as potential PTX-insensitive second messengers at this terminal. Thus, our results suggest that whereas neurotransmitter-mediated calcium channel inhibition is mainly, and possibly exclusively, via G(o)/G(i), other rapid PTX-insensitive G-protein pathways exist that may involve novel, and perhaps transmitter-independent, activating mechanisms.
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PMID:G-Protein types involved in calcium channel inhibition at a presynaptic nerve terminal. 1102 21

In the mammalian CNS, oligodendrocyte precursor cells (OPCs) express most neurotransmitter receptors, but their function remains unclear. The current studies suggest a physiological role for glutamate (AMPA and/or kainate) receptors in OPC migration. AMPA stimulated alphav integrin-mediated OPC migration by increasing both the rate of cell movement and the frequency of Ca2+ transients. A protein complex containing the myelin proteolipid protein (PLP) and alphav integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors resulted in increased association of the AMPA receptor subunits themselves with the alphav integrin/PLP complex. Thus, after AMPA receptor stimulation, an alphav integrin/PLP/neurotransmitter receptor protein complex forms that reduces binding to the extracellular matrix and enhances OPC migration. To assess the extent to which PLP was involved in the AMPA-stimulated migration, OPCs from the myelin-deficient (MD) rat, which has a PLP gene mutation, were analyzed. OPCs from the MD rat had a normal basal migration rate, but AMPA did not stimulate the migration of these cells, suggesting that the PLP/alphav integrin complex was important for the AMPA-mediated induction. AMPA-induced modulation of OPC migration was abolished by pertussis toxin, although baseline migration was normal. Thus, G-protein-dependent signaling is crucial for AMPA-stimulated migration of OPCs but not for basal OPC migration. Other signaling pathways involved in this AMPA-stimulated OPC migration were also determined. These studies highlight novel signaling determinants of OPC migration and suggest that glutamate could play a pivotal role in regulating integrin-mediated OPC migration.
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PMID:Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex. 1651 Jul 24