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 cDNA encoding the platelet-activating factor (PAF) receptor was cloned from a guinea pig lung cDNA library by using a Xenopus laevis oocyte expression system. In the CHO cells which expressed guinea-pig PAF receptor, PAF triggered production of inositol phosphates, the release of arachidonic acid, and inhibited cyclic AMP accumulation. PAF also activated mitogen-activated protein (MAP) kinase and MAP kinase kinase in the CHO cells. These effects were partially regulated by pertussis toxin-sensitive G proteins. The analysis of the human PAF receptor gene revealed that it contains no intron in its coding region, but introns are distributed in the 5'-untranslated region. Two 5'-noncoding exons were identified, which are alternatively spliced to a common splice acceptor site on the third exon to yield two different species of functional mRNA. Existence of distinct promoters may regulated the PAF receptor gene expression in different tissues and cells.
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PMID:[Biological regulation with platelet activating factor--molecular cloning and signal transduction of PAF]. 802 85

The D2 dopamine receptor expressed in the MMQ cell line was characterized by saturation binding using the D2 dopamine radioligand [3H]spiperone. The KD for spiperone was 41 pM and the Bmax for these sites was 34 fmol/mg protein. Inhibition of forskolin-stimulated cAMP accumulation occurred in response to a variety of D2 agonists, and the agonist effects were reversed by D2 antagonists. Pertussis toxin pretreatment abolished agonist inhibition of cAMP accumulation. In addition, the alpha 2-adrenergic agonist UK 14304 inhibited cAMP accumulation; this effect was reversed by an alpha 2-adrenergic antagonist but not by a D2 antagonist, indicating the presence of alpha 2-adrenergic receptors on these cells. Specific oligonucleotide primers were used in the polymerase chain reaction to determine, by restriction enzyme analysis and Southern blotting, that the long form of the two alternatively spliced variants of the D2 dopamine receptor was the predominant variant expressed in these cells.
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PMID:Further characterization of the D2 dopamine receptor expressed in MMQ cells. 810 26

Dopamine D2 receptors both acutely and chronically inhibit high-voltage-activated Ca2+ channels (HVA-CCs). Two alternatively spliced isoforms, D2L (long) and D2S (short), are expressed at high levels in rat pituitary intermediate lobe melanotropes but are lacking in anterior lobe corticotropes. We stably transfected D2L and D2S into corticotrope-derived AtT20 cells. Both isoforms coupled to inhibition of Q-type calcium channels through pertussis toxin-sensitive G proteins. Thus, we have created a model system in which to study the kinetics of D2-receptor regulation of Ca2+ channels. Rapid inhibition of HVA-CCs was characterized using a novel fluorescence video imaging technique for the measurement of millisecond kinetic events. We measured the time elapsed (lag time) between the arrival of depolarizing isotonic 66 mM K+, sensed by fluorescence from included carboxy-X-rhodamine (CXR), and the beginning of increased intracellular Ca2+ levels (sensed by changes in indo 1 fluorescence ratio). The lag time averaged 350-550 ms, with no significant differences among cell types. Addition of the D2-agonist quinpirole (250 microM) to the K+/CXR solution significantly increased the lag times for D2-expressing cells but did not alter the lag time for AtT20 controls. The increased lag times for D2L- and D2S-transfected cells suggest that at least a fraction of the Ca2+ channels was inhibited within the initial 350-550 ms. As this inhibition time is too fast for a multistep second messenger pathway, we conclude that inhibition occurs via a membrane-delimited diffusion mechanism.
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PMID:Dopamine D2-receptor isoforms expressed in AtT20 cells inhibit Q-type high-voltage-activated Ca2+ channels via a membrane-delimited pathway. 993 Jul 19

The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are G(i)alpha protein coupled. MCP-1 induced a transient Ca(2+) flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca(2+) flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca(2+) mobilization, Ca(2+) flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
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PMID:Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. 1104 12

Ca(2+) enters pituitary and pancreatic neuroendocrine cells through dihydropyridine-sensitive channels triggering hormone release. Inhibitory metabotropic receptors reduce Ca(2+) entry through activation of pertussis toxin-sensitive G proteins leading to activation of K(+) channels and voltage-sensitive inhibition of L-type channel activity. Despite the cloning and functional expression of several Ca(2+) channels, those involved in regulating hormone release remain unknown. Using reverse transcription-polymerase chain reaction we identified mRNAs encoding three alpha(1) (alpha(1A), alpha(1C), and alpha(1D)), four beta, and one alpha(2)-delta subunit in rat pituitary GH(3) cells; alpha(1B) and alpha(1S) transcripts were absent. GH(3) cells express multiple alternatively spliced alpha(1D) mRNAs. Many of the alpha(1D) transcript variants encode "short" alpha(1D) (alpha(1D-S)) subunits, which have a QXXER amino acid sequence at their C termini, a motif found in all other alpha(1) subunits that couple to opioid receptors. The other splice variants identified terminate with a longer C terminus that lacks the QXXER motif (alpha(1D-L)). We cloned and expressed the predominant alpha(1D-S) transcript variants in rat brain and GH(3) cells and their alpha(lD-L) counterpart in GH(3) cells. Unlike alpha(1A) channels, alpha(1D) channels exhibited current-voltage relationships similar to those of native GH(3) cell Ca(2+) channels, but lacked voltage-dependent G protein coupling. Our data demonstrate that alternatively spliced alpha(1D) transcripts form functional Ca(2+) channels that exhibit voltage-dependent, G protein-independent facilitation. Furthermore, the QXXER motif, located on the C terminus of alpha(1D-S) subunit, is not sufficient to confer sensitivity to inhibitory G proteins.
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PMID:Functional properties of Cav1.3 (alpha1D) L-type Ca2+ channel splice variants expressed by rat brain and neuroendocrine GH3 cells. 1151 47

A single-nucleotide polymorphism (C825T) in the GNB3 gene produces an alternative splice variant of the heterotrimeric G protein beta3 subunit (Gbeta3). Translation of the alternatively spliced mRNA results in a protein product, Gbeta3-s, in which 41 amino acids are deleted from Gbeta3. Interestingly, previous studies indicate that the C825T allele occurs with a high frequency in patients with certain vascular disorders. However, little information is available regarding the functional role Gbeta3-s might play in ion channel modulation. To examine this aspect, Gbeta3 or Gbeta3-s, along with either Ggamma2 or Ggamma5, were expressed in rat sympathetic neurons by nuclear microinjection of vector encoding the desired protein. In contrast to Gbeta3, expression of Gbeta3-s did not modulate N-type Ca(2+) or G protein-gated inwardly rectifying K(+) channels. In addition, Gbeta3-s did not appear to complex with a pertussis toxin-insensitive mutant of Galpha(i2) or couple to natively expressed alpha(2)-adrenergic receptors. Finally, fluorescence resonance energy transfer (FRET) measurements indicated that enhanced yellow fluorescent protein (EYFP)-labeled Gbeta3-s does not form a Gbetagamma heterodimer when coexpressed with enhanced cyan fluorescent protein (ECFP)-labeled Ggamma2. Therefore, when expressed in sympathetic neurons, Gbeta3-s appears to lack biological activity--hence pathological conditions in patients carrying the homozygous C825T allele may result from a functional knockout of Gbeta3.
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PMID:A splice variant of the G protein beta 3-subunit implicated in disease states does not modulate ion channels. 1270 Mar 59

Octopamine regulates essential processes in nematodes; however, little is known about the physiological role of its precursor, tyramine. In the present study, we have characterized alternatively spliced Caenorhabditis elegans tyramine receptor isoforms (SER-2 and SER-2A) that differ by 23 amino acids within the mid-region of the third intracellular loop. Membranes prepared from cells expressing either SER-2 or SER-2A bind [3H]lysergic acid diethylamide (LSD) in the low nanomolar range and exhibit highest affinity for tyramine. Similarly, both isoforms exhibit nearly identical Ki values for a number of antagonists. In contrast, SER-2A exhibits a significantly lower affinity than SER-2 for other physiologically relevant biogenic amines, including octopamine. Pertussis toxin treatment reduces affinity for both tyramine and octopamine, especially for octopamine in membranes from cells expressing SER-2, suggesting that the conformation of the mid-region of the third intracellular loop is dictated by G-protein interactions and is responsible for the differential tyramine/octopamine affinities of the two isoforms. Tyramine reduces forskolin-stimulated cAMP levels in HEK293 cells expressing either isoform with nearly identical IC50 values. Tyramine, but not octopamine, also elevates Ca2+ levels in cells expressing SER-2 and to a lesser extent SER-2A. Most importantly, ser-2 null mutants (pk1357) fail to suppress head movements while reversing in response to nose-touch, suggesting a role for SER-2 in the regulation of foraging behavior, and fail to respond to tyramine in assays measuring serotonin-dependent pharyngeal pumping. These are the first reported functions for SER-2. These results suggest that C. elegans contains tyramine receptors, that individual SER-2 isoforms may differ significantly in their sensitivity to other physiologically relevant biogenic amines, such as octopamine (OA), and that tyraminergic signaling may be important in the regulation of key processes in nematodes.
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PMID:Tyramine receptor (SER-2) isoforms are involved in the regulation of pharyngeal pumping and foraging behavior in Caenorhabditis elegans. 1556 54

Postganglionic sympathetic nerve terminals innervate cardiac muscle and express opioid receptor-like 1 (ORL1) receptors, the most recently described member of the opioid receptor subclass. ORL1 receptors are stimulated by the endogenous heptadecapeptide nociceptin (Noc). To better understand how the signaling events by Noc regulate sympathetic neuron excitability, the goal of the present study was to determine whether sympathetic stellate ganglion (SG) neurons, innervating the heart, natively express ORL1 opioid receptors and couple to Ca(2+) channels. SG neurons in adult male rats were retrograde-labeled with a fluorescent tracer via injection of the ventricular muscle employing ultrasound imaging. Thereafter, N-type Ca(2+) channel modulation was investigated using the whole-cell variant of the patch-clamp technique. Exposure of labeled SG neurons to Noc resulted in a concentration-dependent inhibition of Ca(2+) currents (with an estimated EC(50) of 193 +/- 14 nM). Pre-exposure of SG neurons to the ORL1 receptor blocker, [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101), significantly decreased the Noc-mediated Ca(2+) current inhibition. The Ca(2+) current inhibition was also blocked by pertussis toxin pretreatment, indicating that signaling occurs via Galpha(i/o) G proteins. Finally, the full-length ORL1 receptor cDNA in SG neurons was cloned and sequenced. Of the two known alternatively spliced variants in rats, sequencing analysis showed that the ORL1 receptor expressed in SG neurons is the short form. Overall, these results suggest that stimulation of postsynaptic ORL1 receptors by Noc in SG neurons regulate cardiac sympathetic activity.
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PMID:Modulation of Ca2+ channels by opioid receptor-like 1 receptors natively expressed in rat stellate ganglion neurons innervating cardiac muscle. 1593 48

Thromboxane A2 receptor (TP) consists of two alternatively spliced isoforms, TPalpha and TPbeta, which differ in their cytoplasmic tails. In the present study, we examined the difference in signal transduction of TPalpha and TPbeta, using stably expressing cells of TPalpha and TPbeta. The cells expressing TPalpha (TPalpha-SC2) and TPbeta (TPbeta-SC15) were selected based on the similar binding sites of [3H]-SQ29548, a TP antagonist. U46619, a TP agonist, elicited phosphoinositide hydrolysis in TPalpha-SC2 and TPbeta-SC15 cells with a similar concentration-dependency. U46619 also caused the phosphorylation of extracellular signal-regulated kinase (ERK1/2) in both TPalpha-SC2 and TPbeta-SC15 cells. While the peak of the phosphorylation of ERK1/2 was observed 5 min after addition of U46619 in TPalpha-SC2 cells, the long lasting phosphorylation up to 60 min was in TPbeta-SC15 cells. U46619-induced phosphorylation of ERK1/2 at 5 min was inhibited by pertussis toxin in both cells, suggesting that G(i) is involved in the phosphorylation mediated via both TP isoforms. Interfering G(12/13) activity by overexpression of p115-RGS reduced U46619-induced ERK1/2 phosphorylation in TPbeta-SC15 cells, but not in TPalpha-SC2 cells. H89, an inhibitor of protein kinase A (PKA), reduced U46619-induced ERK1/2 phosphorylation in TPalpha-SC2 cells, but not in TPbeta-SC15 cells. These results indicate that G(i) may be involved in TP-mediated ERK1/2 phosphorylation in both isoforms. In addition, H89-sensitive kinase and G(12/13) may be involved in TP-mediated ERK1/2 phosphorylation in TPalpha and TPbeta, respectively.
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PMID:Different pathways for activation of extracellular signal-regulated kinase through thromboxane A2 receptor isoforms. 1659 6

Among the three G-protein-linked acetylcholine receptors (GARs) in Caenorhabditis elegans (C. elegans), GAR-3 is structurally and pharmacologically most similar to mammalian muscarinic acetylcholine receptors (mAChRs). Using Chinese hamster ovary (CHO) cells stably expressing GAR-3b, the major alternatively spliced isoform of GAR-3, we observed that carbachol stimulated cyclic AMP (cAMP) production in a dose- and time-dependent manner. The stimulating effect of carbachol was abolished by atropine, a muscarinic antagonist, indicating that the cAMP production is specifically mediated by GAR-3b. When the cells were treated with BAPTA-AM and EGTA, which reduce the cytosolic Ca(2+) level, carbachol-stimulated cAMP accumulation was inhibited by approximately 56%. Inhibition of protein kinase C (PKC) by chronic treatment with phorbol 12-myristate 13-acetate (PMA) or by GF109203X decreased carbachol-stimulated cAMP production by as much as 68%. It thus appears that Ca(2+) and PKC are critically involved in GAR-3b-mediated cAMP formation. We also observed that carbachol-stimulated cAMP production was further enhanced by pertussis toxin (PTX) treatment. This observation indicates that GAR-3b couples to a PTX-sensitive G protein, presumably Gi, to attenuate the cAMP accumulation. Taken together, our data show that GAR-3b stimulates cAMP production in CHO cells and suggest that GAR-3b couples to both stimulatory and inhibitory pathways to modulate the intracellular cAMP level.
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PMID:Stimulation of cyclic AMP production by the Caenorhabditis elegans muscarinic acetylcholine receptor GAR-3 in Chinese hamster ovary cells. 1663 94


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