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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current concepts regarding the regulation and coupling of muscarinic m3 receptors to G-proteins and various effectors are discussed. The last few years have provided much evidence that although muscarinic m1, m3 and m5 subtypes couple predominantly via pertussis toxin-insensitive G-proteins (Gq/11) to activate phosphoinositidase C (PIC), interactions with other G-proteins (Gi, Go, Gs) can be readily observed in cells expressing recombinant muscarinic receptors even at relatively low levels. The significance of this diversity and the potential for agonist "trafficking" could open up opportunities for novel approaches to selective agonist action. Finally, mechanisms underlying the regulation of muscarinic m3 coupling through Gq/11 to PIC are discussed. In particular, our recent studies on precursor lipid depletion, whether regulation is receptor or cell specific and the identification and role of receptor kinases are briefly reviewed.
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PMID:Muscarinic M3 receptor coupling and regulation. 912 45

The regulation of phosphoinositide hydrolysis by the type 1alpha metabotropic glutamate receptor (mGluR1alpha) was investigated in stably transfected baby hamster kidney (BHK) cells. Incubation of the cells with L-glutamate, quisqualate, and 1-aminocyclopentane-1S, 3R-dicarboxylic acid resulted in a marked accumulation of [3H]inositol monophosphate (InsP1) and inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] mass in a time- and concentration-dependent manner. Pretreatment of BHK-mGluR1alpha cells with pertussis toxin [ 100 ng/ml, 24 hr] led to a dramatic 12-16-fold increase in the accumulation of [3H]InsP1 and a 2-fold increase in Ins(1,4,5)P3 in the absence of added agonist. Although only very low levels (</=1 microM) of L-glutamate could be detected in medium taken from control and PTX-treated cell monolayers, the PTX-elicited effect on basal [3H]InsP1 was fully reversed by preincubation of cells in the presence of glutamic-pyruvic transaminase and pyruvate, suggesting that an increased sensitivity to endogenous glutamate was responsible for the apparent agonist-independent activation of phosphoinositidase C (PIC) after PTX treatment. Consistent with this hypothesis, in the presence of glutamic-pyruvic transaminase/pyruvate, the maximal [3H]InsP1 response to quisqualate was increased by >/=75%, and the EC50 shifted leftward by 65-fold [-log EC50 values (molar), 7.26 +/- 0.23 versus 5.45 +/- 0.07; n = 4) in PTX-treated compared with control cells. In contrast, antagonist effects on agonist-stimulated [3H]InsP1 responses were similar in control and PTX-treated BHK-mGluR1alpha cells. These changes in the concentration-effect curves for mGluR agonists are consistent with a model in which the receptor associates with PTX-sensitive inhibitory (Gi/o) and PTX-insensitive stimulatory (Gq/11) G proteins that can each influence PIC activity. The present observations are consistent with a dual regulation of mGluR1alpha-mediated PIC activity that could be fundamental in controlling the output of phosphoinositide-derived messengers.
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PMID:Enhanced type 1alpha metabotropic glutamate receptor-stimulated phosphoinositide signaling after pertussis toxin treatment. 928 2

X-ray microanalysis was used to investigate whether cAMP- and/or Ca2+-activated regulation of chloride and potassium efflux is expressed in primary cultures of sweat gland duct cells. The effects of extracellular UTP and ATP on the duct cells, and the signalling system involved in the response to ATP was also studied. Primary cultures from duct cells of human sweat glands responded to 1 microM carbachol, 2 microM of the Ca2+ ionophore A23187, or 5 mM 8-bromo-cAMP stimulation for 5 min, resulting in a decrease in cellular Cl and K concentrations. 50 microM 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid (NPPB), a Cl- channel blocker, can inhibit the decrease in Cl concentration induced by cAMP. Extracellular (200 microM) ATP caused a decrease of Cl and K in cultured duct cells, while (200 microM and 2 mM) UTP was ineffective. Both the phosphoinositidase C inhibitor U73122 (10 microM) and the absence of extracellular Ca2+ abolished the ATP-induced decrease in Cl and K content. Alloxan (1.25 mM), an adenylate cyclase inhibitor, had an inhibitory effect on the response to ATP. The decrease in K, but not in Cl, content in the cells elicited by ATP was blocked by prior incubation with 100 ng/ml pertussis toxin, indicating the coupling of ATP to pertussis toxin-sensitive G-proteins. In conclusion, both Ca2+- and cAMP-dependent Cl- permeability is present in primary cultures from duct cells of human sweat gland. The response to ATP can be mediated both by Ca2+- and by cAMP-dependent pathways, and is coupled to pertussis toxin-sensitive G-proteins.
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PMID:Regulation of ion content in primary cultures from reabsorptive ducts of human sweat glands studied by X-ray microanalysis. 987 64

Previous reports on heterologously-expressed human P2Y11 receptors have indicated that ATP, but not UTP, is an agonist stimulating both phosphoinositidase C and adenylyl cyclase. Consistent with these findings, we report that in 1321N1 cells expressing human P2Y11 receptors, UTP stimulation did not lead to accumulation of inositol(poly)phosphates under conditions in which ATP gave a robust, concentration-dependent effect. Unexpectedly, however, both UTP and ATP stimulated increases in cytosolic Ca2+ concentration ([Ca2+]c), with both nucleotides achieving similar EC50 and maximal responses. The responses to maximally effective concentrations of ATP and UTP were not additive. The [Ca2+]c increase in response to UTP was less dependent on extracellular Ca2+ than was the response to ATP. AR-C67085 (2-propylthio-beta,gamma-difluoromethylene-d-ATP, a P2Y11-selective agonist), adenosine 5'-O-(3-thiotriphosphate), and benzoyl ATP were all full agonists with potencies similar to those of ATP and UTP. In desensitization experiments, exposure to ATP resulted in loss of the UTP response; this response was more sensitive to desensitization than that of ATP. Pertussis toxin pretreatment attenuated the response to UTP but left the ATP response unaffected. The presence of 2-aminoethyl diphenylborate differentially affected the responses of ATP and UTP. No mRNA transcripts for P2Y2 or P2Y4 were detectable in the P2Y11-expressing cells. We conclude that UTP is a Ca2+-mobilizing agonist at P2Y11 receptors and that ATP and UTP acting at the same receptor recruit distinct signaling pathways. This example of agonist-specific signaling is discussed in terms of agonist trafficking and differential signal strength.
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PMID:Characterization of a Ca2+ response to both UTP and ATP at human P2Y11 receptors: evidence for agonist-specific signaling. 1276 46


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