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

The large gene family encoding the regulators of G protein signaling (RGS) proteins has been implicated in the fine tuning of a variety of cellular events in response to G protein-coupled receptor activation. Several studies have shown that the RGS proteins can attenuate G protein-activated extracellular signal-regulated kinase (ERK) group of mitogen-activated protein kinases. We demonstrate herein that the production of inositol trisphosphate and the activation of the p38 group of mitogen-activated protein kinases by the G protein-coupled platelet-activating factor (PAF) receptor was attenuated by RGS16 in both CHO cells transiently and stably expressing RGS16. The inhibition was not observed with RGS2, RGS5, and a functionally defective form of RGS16, RGS16(R169S/F170C). The PAF-induced p38 and ERK pathways appeared to be preferentially regulated by RGS16 and RGS1, respectively. Overexpression of a constitutively active form of Galpha11 (Galpha11Q209L) prevented the RGS16-mediated attenuation of p38 activity, suggesting that Galphaq/11 is involved in PAF activation of p38. The Galphaq/11 involvement is further supported by the observation that p38 activation by PAF was pertussis toxin-insensitive. These results demonstrate for the first time that apart from ERK, p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence for the specificity of RGS function in G protein signaling pathways.
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PMID:RGS16 attenuates galphaq-dependent p38 mitogen-activated protein kinase activation by platelet-activating factor. 991 20

Group I mGluRs heterologously expressed in sympathetic neurons inhibited calcium (I(Ca)) and M-type potassium (I(M)) currents. Treatment with pertussis toxin (PTX) revealed a voltage-dependent (VD), PTX-sensitive component of I(Ca) inhibition and a voltage-independent (VI), PTX-insensitive component. Coexpression of RGS2 occluded mGluR1a inhibition of I(M) and made I(Ca) inhibition VD in PTX-treated cells, presumably by blocking the effects of G alpha(q/11)-GTP. These data indicate that mGluR1a can couple to G(i/o) as well as G(q/11). In addition, VI I(Ca) inhibition proceeds through a G alpha(q/11)-GTP-mediated pathway, which can be occluded by expressing RGS2, leaving the VD, G betagamma-mediated inhibition active. These data may reveal a functional role for the upregulation of RGS2 expression in in vivo systems.
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PMID:Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels. 1023 Aug 1

1. The activation of G protein-regulated inward rectifying potassium (GIRK) channels is modulated by G protein-coupled receptors (GPCRs) via the G protein betagamma subunits and is accelerated by regulators of G protein signalling (RGS). In the present study we investigated the ratio dependence of receptor-mediated activation and deactivation and the influence of new members of the RGS protein family on GIRK currents by coexpressing the recombinant protein subunits in Xenopus oocytes and further analysis of the whole cell currents. 2. The activation of GIRK channels by the muscarinic acetylcholine receptor M2 (M2 mAChR) is strongly dependent on the ratio of receptor to channel in Xenopus oocytes. The increase and on-rate of the amplified current is affected by this ratio. An excess of receptor over channel is necessary for current amplification, while the reverse excess of channel over receptor abolishes the effect. 3. The speed of receptor-mediated activation of GIRK currents is accelerated for a high ratio of receptor to channel, while the time of deactivation is independent of this ratio. 4. Coexpression of RGS2, 5 and 8 accelerates the speed for ACh-mediated activation and deactivation of GIRK1/2 and GIRK1/4 currents. Thereby the receptor/channel/RGS ratio determines the amount of current amplification. 5. Bordetella pertussis toxin completely abolished ACh-mediated current amplification of GIRK channels coexpressed with or without RGS2. 6. Two single point mutations in the RGS2 protein (RGS2(N109S) and RGS2(L180F)) reduced the acceleration of current amplification after ACh application on GIRK1/4 channels compared with RGS2 wild-type protein.
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PMID:New roles for RGS2, 5 and 8 on the ratio-dependent modulation of recombinant GIRK channels expressed in Xenopus oocytes. 1033 86

Calcium current modulation by the muscarinic cholinergic agonist oxotremorine methiodide (oxo-M) was examined in sympathetic neurons from the superior cervical ganglion of the rat. Oxo-M strongly inhibited calcium currents via voltage-dependent (VD) and voltage-independent (VI) pathways. These pathways could be separated with the use of the specific M(1) acetylcholine receptor antagonist M(1)-toxin and with pertussis toxin (PTX) treatment. Expression by nuclear cDNA injection of the regulator of G-protein signaling (RGS2) or a phospholipase Cbeta1 C-terminal construct (PLCbeta-ct) selectively reduced VI oxo-M modulation in PTX-treated and untreated cells. Expression of the Gbetagamma buffers transducin (Galpha(tr)) and a G-protein-coupled-receptor kinase (GRK3) construct (MAS-GRK3) eliminated oxo-M modulation. Activation of the heterologously expressed neurokinin type 1 receptor, a Galpha(q/11)-coupled receptor, resulted in VI calcium current modulation. This modulation was eliminated with coexpression of Galpha(tr) or MAS-GRK3. Cells expressing Gbeta(1)gamma(2) were tonically inhibited via the VD pathway. Application of oxo-M to these cells produced VI modulation and reduced the amount of current inhibited via the VD pathway. Together, these results confirm the requirement for Gbetagamma in VD modulation and implicate Galpha(q)-GTP and Gbetagamma as components in the potentially novel VI pathway.
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PMID:A voltage-independent calcium current inhibitory pathway activated by muscarinic agonists in rat sympathetic neurons requires both Galpha q/11 and Gbeta gamma. 1090 99

1. Members of the Kir3.0 family of inwardly rectifying K(+) channels are expressed in neuronal, atrial and endocrine tissues and play key roles in generating late inhibitory postsynaptic potentials (IPSPs), slowing heart rate and modulating hormone release. They are activated directly by G(betagamma) subunits released in response to G(i/o)-coupled receptor stimulation. However, it is not clear to what extent this process can be dynamically regulated by other cellular signalling systems. In this study we have explored pathways activated by the G(q/11)-coupled M(1) and M(3) muscarinic receptors and their role in the regulation of Kir3.1+3.2A neuronal-type channels stably expressed in the human embryonic kidney cell line HEK293. 2. We describe a novel biphasic pattern of behaviour in which currents are initially stimulated but subsequently profoundly inhibited through activation of M(1) and M(3) receptors. This contrasts with the simple stimulation seen through activation of M(2) and M(4) receptors. 3. Channel stimulation via M(1) but not M(3) receptors was sensitive to pertussis toxin whereas channel inhibition through both M(1) and M(3) receptors was insensitive. In contrast over-expression of the C-terminus of phospholipase Cbeta1 or a G(q/11)-specific regulator of G protein signalling (RGS2) essentially abolished the inhibitory phase. 4. The inhibitory effects of M(1) and M(3) receptor stimulation were mimicked by phorbol esters and a synthetic analogue of diacylglycerol but not by the inactive phorbol ester 4alphaphorbol. Inhibition of the current by a synthetic analogue of diacylglycerol effectively occluded any further inhibition (but not activation) via the M(3) receptor. 5. The receptor-mediated inhibitory phenomena occur with essentially equal magnitude at all intracellular calcium concentrations examined (range, 0-669 nM). 6. The expression of endogenous protein kinase C (PKC) isoforms in HEK293 cells was examined by immunoblotting, and their translocation in response to phorbol ester treatment by cellular extraction. The results indicated the expression and translocation of the novel PKC isoforms PKCdelta and PKCepsilon. 7. We also demonstrate that activation of such a pathway via both receptor-mediated and receptor-independent means profoundly attenuated subsequent channel stimulation by G(i/o)-coupled receptors. 8. Our data support a role for a Ca(2+)-independent PKC isoform in dynamic channel regulation, such that channel activity can be profoundly reduced by M(1) and M(3) muscarinic receptor stimulation.
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PMID:Regulation of a G protein-gated inwardly rectifying K+ channel by a Ca(2+)-independent protein kinase C. 1145 57

Regulators of G protein signaling (RGS) proteins compose a highly diverse protein family best known for inhibition of G protein signaling by enhancing GTP hydrolysis by Galpha subunits. Little is known about the function of endogenous RGS proteins. In this study, we used synthetic ribozymes targeted to RGS2, RGS3, RGS5, and RGS7 to assess their function. After demonstrating the specificity of in vitro cleavage by the RGS ribozymes, rat aorta smooth muscle cells were used for transient transfection with the RGS-specific ribozymes. RGS3 and RGS5 ribozymes differentially enhanced carbachol- and angiotensin II-induced MAP kinase activity, respectively, whereas RGS2 and RGS7 ribozymes had no effect. This enhancement was pertussis toxin-insensitive. Thus RGS3 is a negative modulator of muscarinic m3 receptor signaling, and RGS5 is a negative modulator of angiotensin AT1a receptor signaling through G(q/11). Also, RGS5 ribozyme enhanced angiotensin-stimulated inositol phosphate release. These results indicate the feasibility of using the ribozyme technology to determine the functional role of endogenous RGS proteins in signaling pathways and to define novel receptor-selective roles of endogenous RGS3 and RGS5 in modulating MAP kinase responses to either carbachol or angiotensin.
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PMID:Receptor-selective effects of endogenous RGS3 and RGS5 to regulate mitogen-activated protein kinase activation in rat vascular smooth muscle cells. 1200 2

Ca(2+) influx through L-type channels is critical for numerous physiological functions. Relatively little is known about modulation of neuronal L-type Ca(2+) channels. We studied modulation of neuronal Ca(V)1.2c channels heterologously expressed in HEK293 cells with each of the known muscarinic acetylcholine receptor subtypes. Galphaq/11-coupled M1, M3, and M5 receptors each produced robust inhibition of Ca(V)1.2c, whereas Galphai/o-coupled M2 and M4 receptors were ineffective. Channel inhibition through M1 receptors was studied in detail and was found to be kinetically slow, voltage-independent, and pertussis toxin-insensitive. Slow inhibition of Ca(V)1.2c was blocked by coexpressing RGS2 or RGS3T or by intracellular dialysis with antibodies directed against Galphaq/11. In contrast, inhibition was not reduced by coexpressing betaARK1ct or Galphat. These results indicate that slow inhibition required signaling by Galphaq/11, but not Gbetagamma, subunits. Slow inhibition did not require Ca(2+) transients or Ca(2+) influx through Ca(V)1.2c channels. Additionally, slow inhibition was insensitive to pharmacological inhibitors of phospholipases, protein kinases, and protein phosphatases. Intracellular BAPTA prevented slow inhibition via a mechanism other than Ca(2+) chelation. The cardiac splice-variant of Ca(V)1.2 (Ca(V)1.2a) and a splice-variant of the neuronal/neuroendocrine Ca(V)1.3 channel also appeared to undergo slow muscarinic inhibition. Thus, slow muscarinic inhibition may be a general characteristic of L-type channels having widespread physiological significance.
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PMID:Reconstituted slow muscarinic inhibition of neuronal (Ca(v)1.2c) L-type Ca2+ channels. 1249 94

In neuronal cells, the influx of Ca2+ ions through voltage-dependent L-type calcium (L) channels couples excitation to multiple cellular functions. In addition to voltage, several neurotransmitters, hormones and cytokines regulate L channel gating via binding to G-protein-coupled receptors. Intracellular molecules that modify G-protein activity - such as regulator of G-protein-signalling (RGS) proteins - are therefore potential candidates for regulating Ca2+ influx through L channels. Here we show that a novel RGS2 splice variant from chick dorsal root ganglion (DRG) neurons, RGS2L, reduces bradykinin (BK)-mediated inhibition of neuronal L channels and accelerates recovery from inhibition. Chick RGS2 reduces the inhibition mediated by both the pertussis toxin (PTX)-sensitive (Gi/o-coupled) and the PTX-insensitive (presumably Gq/11-coupled) pathways. However, we demonstrate for the first time in a living cell that the extent of coupling to each pathway varies with RGS2L concentration. A low concentration of recombinant chick RGS2L (10 nM) preferentially reduces the inhibition mediated by the PTX-insensitive pathway, whereas a 100-fold higher concentration attenuates both PTX-sensitive- and PTX-insensitive-mediated components equally. Our data suggest that factors promoting RGS2L gene induction may regulate Ca2+ influx through L channels by recruiting low-affinity interactions with Gi/o that are absent at basal RGS2L levels.
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PMID:Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels. 1265 16

Using adenoviruses encoding RGS2, RGS4 and Lsc (regulator of G protein signalling (RGS) domain of p115 RhoGEF), we investigated the contributions of G(q/11), Gi and G(12/13) proteins to G protein-coupled receptor (GPCR)-mediated activation of the extracellular signal-regulated kinase (ERK) pathway in adult rat ventricular myocytes (ARVM). Exposure to phenylephrine, endothelin-1 (ET-1) or thrombin induced significant activation of ERK1/2 and their downstream target 90 kDa ribosomal S6 kinase (p90RSK), which was abolished by overexpression of RGS4 (inhibits signalling via G(q/11) and Gi) or RGS2 (inhibits signalling via G(q/11)). Pertussis toxin (inhibits signalling via Gi) only partially attenuated the activation of ERK1/2 and p90(RSK) by phenylephrine and ET-1, but abolished such activation by thrombin. Overexpression of Lsc (inhibits signalling via G(12/13)) did not affect the responses to phenylephrine and ET-1, but suppressed the activation of ERK1/2 and p90RSK by thrombin. We conclude that full activation of the ERK pathway in ARVM by alpha1-adrenergic, ET-1 and thrombin receptors requires the activation of distinct families of heterotrimeric G proteins.
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PMID:Regulation of the extracellular signal-regulated kinase pathway in adult myocardium: differential roles of G(q/11), Gi and G(12/13) proteins in signalling by alpha1-adrenergic, endothelin-1 and thrombin-sensitive protease-activated receptors. 1568 40

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of beta-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Galpha(q)-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.
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PMID:Identification of a novel extracellular cation-sensing G-protein-coupled receptor. 1619 32


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