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)

The AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism. We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods. In neurons dialyzed with GTP, L-AP4 inhibited high-threshold calcium currents evoked in barium solutions. The inhibition was irreversible in the presence of GTP-gamma-S and blocked by removing intracellular Mg2+ or by preincubation with pertussis toxin (PTX), consistent with the involvement of a PTX-sensitive G-protein. Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions. PTX also blocked the L-AP4-induced inhibition of monosynaptic EPSPs evoked by intracellular stimulation of cultured mitral cells. These results suggest that the presynaptic AP4 receptor is a G-protein-coupled glutamate receptor, and that inhibition of calcium influx by a membrane-delimited action of a G-protein may account for L-AP4-induced presynaptic inhibition.
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PMID:L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor. 131 54

We have previously reported the selective amplification of several rat striatal cDNA sequences that encode guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. One of these sequences (R226) exhibited high sequence identity (58%) with the two previously cloned adenosine receptors. A full-length cDNA clone for R226 has been isolated from a rat brain cDNA library. The cDNA clone encodes a protein of 320 amino acids that can be organized into seven transmembrane stretches. R226 has been expressed in COS-7 and CHO cells and membranes from the transfected cells were screened with adenosine receptor radioligands. R226 could bind the nonselective adenosine agonist tritiated N-ethyladenosine 5'-uronic acid ([3H]NECA) and A1-selective agonist radioiodinated N6-2-(4-amino-3-iodophenyl)-ethyladenosine ([125I]APNEA) but not A1-selective antagonists tritiated 1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) and 8-(4-[([[(2-aminoethyl)amino]carbonyl]methyl)oxy]-phenyl)-1, 3-dipropylxanthine ([3H]XAC) or the A2-selective agonist ligands tritiated 2-[4-(2-carboxyethyl)phenyl]ethyl-amino 5'-N-ethylcarboxamidoadenosine ([3H]CGS21680) and radioiodinated 2-[4-([2-[(4-aminophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl)phenyl]ethylamino 5'-N-ethylcarboxamidoadenosine. Extensive characterization with [125I]APNEA showed that R226 binds [125I]APNEA with high affinity (Kd = 15.5 +/- 2.4 nM) and the specific [125I]APNEA binding could be inhibited by adenosine ligands with a potency order of (R)-N6-phenyl-2-propyladenosine (R-PIA) = NECA greater than S-PIA greater than adenosine greater than ATP = ADP but not by antagonists XAC, isobutylmethylxanthine, and DPCPX. In R226 stably transfected CHO cells, adenosine agonists R-PIA, NECA, and CGS21680 inhibited by 40-50% the forskolin-stimulated cAMP accumulation through a pertussis toxin-sensitive G protein with an EC50 of 18 +/- 5.6 nM, 23 +/- 3.5 nM, and 144 +/- 34 nM, respectively. Based on these observations we conclude that R226 encodes an adenosine receptor with non-A1 and non-A2 specificity, and we thus name it the A3 adenosine receptor. mRNA analyses revealed that the highest expression of R226 was in the testis and low-level mRNAs were also found in the lung, kidneys, heart, and some parts of the central nervous system such as cortex, striatum, and olfactory bulb. The high-expression level of the A3 receptor in the testis suggests a possible role for adenosine in reproduction.
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PMID:Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. 132 36

The gene encoding a novel mouse somatostatin receptor termed mSSTR3 was isolated and characterized. The sequence of mSSTR3 shows 46 and 47% identity with mSSTR1 and mSSTR2, respectively. mSSTR3 binds somatostatin-14 and somatostatin-28 with high affinity, but shows very low affinity for the somatostatin analogs MK-678 and SMS-201-995. In addition, mSSTR3 is coupled to pertussis toxin-sensitive G proteins and mediates somatostatin inhibition of forskolin-stimulated and dopamine D1 receptor-stimulated cAMP formation, indicating that it is coupled to adenylylcyclase. The pharmacological properties of mSSTR3 and its ability to couple with adenylylcyclase distinguish SSTR3 from the other cloned somatostatin receptors and indicates that it mediates biological functions different from SSTR1 or SSTR2. In situ hybridization indicates that SSTR3 mRNA is widely distributed in the mouse brain, and its expression in the nucleus of the lateral olfactory tract and in the piriform cortex, the primary olfactory cortex in the rodent brain, suggests that SSTR3 may participate in the processing and modulation of primary sensory information.
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PMID:Cloning of a novel somatostatin receptor, SSTR3, coupled to adenylylcyclase. 132 99

The muscarinic stimulation of adenylate cyclase activity in rat olfactory bulb was characterized, with the aim of elucidating the nature of the molecular mechanism involved. Carbachol (CCh) stimulated the enzyme activity in either crude or purified cell membrane preparations and increased cyclic AMP accumulation in miniprisms of olfactory bulb. The CCh stimulation of adenylate cyclase activity displayed a fast onset and was rapidly reversed by addition of atropine. The stimulation was associated with an increase in the apparent Vmax of the enzyme, with no change in the Km for Mg-ATP. The affinity of the enzyme for Mg2+ was enhanced by CCh. The muscarinic effect required GTP at concentrations higher than those needed for enzyme stimulation with either l-isoproterenol or vasoactive intestinal peptide. Moreover, contrary to the beta-adrenergic stimulation, the muscarinic effect disappeared when guanosine 5'-O-(3'-thiotriphosphate) was substituted for GTP. In vivo treatment of olfactory bulbs with pertussis toxin completely prevented the muscarinic stimulation of adenylate cyclase, whereas cholera toxin was without effect. These results indicate that in rat olfactory bulb muscarinic receptors increase adenylate cyclase activity by interacting with a pertussis toxin-sensitive GTP-binding protein different from the stimulatory GTP-binding protein.
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PMID:Properties of muscarinic-stimulated adenylate cyclase activity in rat olfactory bulb. 137 77

The most pronounced effect of norepinephrine (NE) in the olfactory bulb is disinhibition of mitral/tufted (M/T) cells. Although it has been previously proposed that the effects of NE are mediated by a direct inhibitory action on granule cells, we have demonstrated that NE could exert it effects through inhibition of excitatory synaptic transmission from M/T cells to granule cells (Trombley and Shepherd, 1992). In order to define further the mechanism underlying NE-mediated inhibition of synaptic transmission, the effects of NE on calcium channel currents were examined using whole-cell recording techniques on bulb neurons in primary culture. NE inhibited high-threshold calcium currents at concentrations that were effective in reducing synaptic transmission. Clonidine, but not isoproterenol, mimicked the effects of NE on calcium currents, suggesting that the effects were mediated through activation of presynaptic alpha-adrenergic receptors. The effects of NE on calcium currents were irreversible in the presence of internal GTP-gamma S and prevented by preincubation with pertussis toxin, results that are consistent with a G-protein-coupled mechanism. Preincubation with pertussis toxin also prevented the effects of NE on synaptic transmission, suggesting that a similar G-protein couple mechanism mediates both effects. Intracellular dialysis with staurosporin or calcium buffering with EGTA did not prevent the effects of NE, suggesting that neither protein phosphorylation nor elevated intracellular calcium were required. These results suggest that NE may inhibit synaptic transmission in the olfactory bulb by reducing calcium currents via a G-protein-coupled alpha-adrenergic receptor.
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PMID:Norepinephrine inhibits calcium currents and EPSPs via a G-protein-coupled mechanism in olfactory bulb neurons. 140 95

In homogenate of rat olfactory bulb, the opioid receptor agonists beta-endorphin, Leu-enkephalin, and dynorphin A stimulated adenylate cyclase activity in a concentration-dependent manner, with half-maximal effects displayed at 22, 63, and 176 nM, respectively. The maximal stimulation of the enzyme activity corresponded to about a 40% increase of basal activity for all three peptides. Naloxone antagonized the stimulation of beta-endorphin, Leu-enkephalin, and dynorphin A, with pA2 values of 8.0, 7.7, and 8.1, respectively. Kinetic analysis performed with Leu-enkephalin showed that the opioid peptide increased the Vmax of the enzyme, without changing the Km for the substrate Mg-ATP. Moreover, the opioid stimulation was associated with a significant increase of the affinity of the enzyme for Mg2+ activation and occurred in membranes incubated in a Ca2(+)-free medium. Addition of exogenous GTP at micromolar concentrations was absolutely necessary for the detection of the opioid effect. Treatment of olfactory bulbs with cholera toxin did not alter the stimulation of adenylate cyclase by Leu-enkephalin. However, the opioid stimulation disappeared in membranes obtained from bulbs injected with pertussis toxin. These results demonstrate the presence in the brain of a new functional class of opiate receptors coupled to stimulation of adenylate cyclase via a transduction mechanism that is Ca2+ independent and seems to involve a pertussis toxin-sensitive GTP-binding protein.
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PMID:Naturally occurring opioid receptor agonists stimulate adenylate cyclase activity in rat olfactory bulb. 167 23

Nine distinct alpha subunits of guanine nucleotide binding proteins (G-proteins) have now been identified by cDNA cloning. Each of these functions to allow transduction of information between hormone-activated receptors in the plasma membrane and effector systems which are either ion channels or enzymes which regulate the intracellular concentration of second messengers. As the individual G-proteins are highly similar in primary sequence, it is pertinent to ask what degree of specificity of interaction each of these display with the various receptors and effector systems. Specificity of tissue location defines that the rod and cone transducins (TD1 and TD2, respectively) act as the coupling proteins between rhodopsin and cone opsins and their cyclic nucleotide phosphodiesterase effectors and that G(olf) is the G-protein which tranduces signals from odorant receptors to adenylate cyclase in olfactory sensory neurones. However, many of the other identified G-proteins are co-expressed in a single tissue or cell. Whilst sensitivity to ADP-ribosylation catalysed by bacterial toxins from Bordetella pertussis and Vibrio cholerae has allowed a further subdivision of the G-protein family, this approach is limited as these toxins have multiple G-protein substrates. As the extreme C-terminus of the alpha subunit of each G-protein appears to be a key domain for the interactions of receptors and G-proteins we have generated a series of G-protein-selective antipeptide antisera against this region and then have used these antisera to attempt to interfere with receptor-G-protein coupling. With this approach we have been able to demonstrate that a delta opioid receptor-mediated inhibition of adenylate cyclase in neuroblastoma x glioma, NG108-15, cell membranes is transduced specifically by Gi2 and in the same cell that alpha 2 adrenergic inhibition of Ca2+ currents is transduced by Go. Similar strategies are likely to be of universal significance, for example in the identification of the G-protein (Gp) which regulates the receptor-mediated activation of phosphoinositidase C. Methods to allow pharmacological manipulation of the levels of expression of various G-proteins in the membranes of cells are also discussed. Such approaches are also likely to assist in the identification of G-proteins of defined functions.
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PMID:The role and specificity of guanine nucleotide binding proteins in receptor-effector coupling. 196 33

In superfused striatal synaptosomes, previously unexposed to Ca2+ during isolation and superfusion, 1.25 mM Ca2+ evokes the release of [3H]dopamine. This Ca2+-evoked release is produced without elevating K+ (4.5 mM) before or after Ca2+ exposure, can be blocked by the Na+ channel antagonist tetrodotoxin, and modulated by dopamine (D2) receptor agonists and antagonists. We now present evidence that functional K+ channels regulate Ca2+-evoked [3H]dopamine release and may be necessary for the dopamine (D2) modulation of this release. The K+ channel blocker tetraethyl ammonium (TEA) could partially prevent D2 agonist (LY-171555) inhibition of Ca2+-evoked release in both olfactory tubercle and striatal synaptosomes. Another K+ channel blocker, 4-aminopyridine, also partially blocked dopamine (D2) agonist inhibition of release. When both 5 mM tetraethyl ammonium and 0.1 mM 4-aminopyridine were employed, by, dopamine (D2) inhibition of Ca2+-evoked [3H]dopamine release was prevented. However, with both K+ channel blockers present, only the initial portion of the release could be blocked by tetrodotoxin. These results are consistent with what might be expected if K+ channels were linked to dopamine (D2) receptors. In additional experiments we found that stimulation of adenylate cyclase by 1 microM forskolin with 0.25 mM 3-isobutyl-1-methylxanthine present potentiated Ca2+-evoked [3H]dopamine release but that this combination did not affect dopamine (D2) inhibition of [3H]dopamine release. Furthermore, although the protein alkylator n-ethylmaleimide could block dopamine (D2) inhibition of release, pertussis toxin, a specific inactivator of the inhibitory protein regulating adenylate cyclase, had little effect on dopamine (D2) inhibition. Therefore, dopamine (D2) inhibition of dopamine release may not be coupled to adenylate cyclase activity.
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PMID:K+ channel and adenylate cyclase involvement in regulation of Ca2+-evoked release of [3H]dopamine from synaptosomes. 246 5

GTP-binding regulatory proteins (G-proteins) were identified in chemosensory membranes from the channel catfish, Ictalurus punctatus. The common G-protein beta-subunit was identified by immunoblotting in both isolated olfactory cilia and purified taste plasma membranes. A cholera toxin substrate (Mr 45,000), corresponding to the G-protein that stimulates adenylate cyclase, was identified in both membranes. Both membranes also contained a single pertussis toxin substrate. In taste membranes, this component co-migrated with the alpha-subunit of the G-protein that inhibits adenylate cyclase. In olfactory cilia, the Mr 40,000 pertussis toxin substrate cross-reacted with antiserum to the common amino acid sequence of G-protein alpha-subunits, but did not cross-react with antiserum to the alpha-subunit of the G-protein from brain of unknown function. The interaction of G-proteins with chemosensory receptors was determined by monitoring receptor binding affinity in the presence of exogenous guanine nucleotides. L-Alanine and L-arginine bind with similar affinity to separate receptors in both olfactory and gustatory membranes from the catfish. GTP and a nonhydrolyzable analogue decreased the affinity of olfactory L-alanine and L-arginine receptors by about 1 order of magnitude. In contrast, the binding affinities of the corresponding taste receptors were unaffected. These results suggest that olfactory receptors are functionally coupled to G-proteins in a manner similar to some hormone and neurotransmitter receptors.
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PMID:Interaction of GTP-binding regulatory proteins with chemosensory receptors. 310 71

In the presence of activated Gs alpha, the beta gamma complex of heterotrimeric G proteins (beta gamma) stimulates adenylyl cyclase (AC) in membranes prepared from cells expressing recombinant AC II or AC IV. Conditional stimulation of AC by beta gamma has been hypothesized to integrate cross-talk between Gs- and non-Gs-coupled regulation of cellular cAMP (Tang, W. J., and Gilman, A. G. (1991) Science 254, 1500-1503). Although observations in cells expressing recombinant receptors, G alpha s, and AC support this hypothesis (Federman, A. D., Conklin, B. R., Schrader, K. A., Reed, R. R., and Bourne, H. R. (1992) Nature 356, 159-161), this mechanism has not been investigated in differentiated cells. Expression of AC II has been reported only in lung, olfactory, and brain tissue. We found that rat lung alveolar type II cells express AC II and IV. Therefore, we hypothesized that beta gamma conditionally stimulates AC in type II cells. Consistent with this hypothesis, we found that the alpha 2-adrenergic agonist UK14304 did not affect basal cAMP in type II cells but potentiated terbutaline-stimulated cAMP accumulation. Treatment of cells with pertussis toxin partially inhibited terbutaline-stimulated cAMP accumulation and completely inhibited the effects of UK14304. In type II cell membranes, purified beta gamma tripled the terbutaline-stimulated increase in AC activity. In contrast, beta gamma inhibited AC activity in the absence of terbutaline. The addition of purified Go alpha blocked beta gamma-induced effects. In summary, type II cells expressing endogenous AC II and IV regulate cAMP accumulation and AC activity in a manner consistent with conditional stimulation by beta gamma. These observations support the overall hypothesis that conditional stimulation of AC by beta gamma integrates cross-talk between signal transduction systems in differentiated cells.
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PMID:Evidence for G beta gamma-mediated cross-talk in primary cultures of lung alveolar cells. Pertussis toxin-sensitive production of cAMP. 770 88


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