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)

Ca2+ ion concentration changes are critical events in signal transduction. The Ca2+-dependent interactions of calmodulin (CaM) with its target proteins play an essential role in a variety of cellular functions. In this study, we investigated the interactions of G protein betagamma subunits with CaM. We found that CaM binds to known betagamma subunits and these interactions are Ca2+-dependent. The CaM-binding domain in Gbetagamma subunits is identified as Gbeta residues 40-63. Peptides derived from the Gbeta protein not only produce a Ca2+-dependent gel mobility shifting of CaM but also inhibit the CaM-mediated activation of CaM kinase II. Specific amino acid residues critical for the binding of Gbetagamma to CaM were also identified. We then investigated the potential function of these interactions and showed that binding of CaM to Gbetagamma inhibits the pertussis toxin-catalyzed ADP-ribosylation of Galphao subunits, presumably by inhibiting heterotrimer formation. Furthermore, we demonstrated that interaction with CaM has little effect on the activation of phospholipase C-beta2 by Gbetagamma subunits, supporting the notion that different domains of Gbetagamma are responsible for the interactions of different effectors. These findings shed light on the molecular basis for the interactions of Gbetagamma with Ca2+-CaM and point to the potential physiological significance of these interactions in cellular functions.
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PMID:The Ca2+-dependent binding of calmodulin to an N-terminal motif of the heterotrimeric G protein beta subunit. 922 54

Recently, we have isolated a cDNA encoding a muscarinic acetylcholine receptor (mAChR) from Caenorhabditis elegans. To investigate the regulation of phospholipase D (PLD) signaling via a muscarinic receptor, we generated stable transfected Chinese hamster ovary (CHO) cells that overexpress the mAChR of C. elegans (CHO-GAR-3). Carbachol (CCh) induced inositol phosphate formation and a significantly higher Ca(2+) elevation and stimulated PLD activity through the mAChR; this was insensitive to pertussis toxin, but its activity was abolished by the phospholipase C (PLC) inhibitor U73122. Western blot analysis revealed several apparent tyrosine-phosphorylated protein bands after CCh treatment. The CCh-induced PLD activation and tyrosine phosphorylation were significantly reduced by the protein kinase C (PKC) inhibitor calphostin C and down-regulation of PKC and the tyrosine kinase inhibitor genistein. Moreover, the Ca(2+)-calmodulin-dependent protein kinase II (CaM kinase II) inhibitor KN62, in addition to chelation of extracellular or intracellular Ca(2+) by EGTA and BAPTA/AM, abolished CCh-induced PLD activation and protein tyrosine phosphorylation. Taken together, these results suggest that the PLC/PKC-PLD pathway and the CaM kinase II/tyrosine kinase-PLD pathway are involved in the activation of PLD through mAChRs of C. elegans.
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PMID:Phospholipase C, protein kinase C, Ca(2+)/calmodulin-dependent protein kinase II, and tyrosine phosphorylation are involved in carbachol-induced phospholipase D activation in Chinese hamster ovary cells expressing muscarinic acetylcholine receptor of Caenorhabditis elegans. 1085 71

The myogenic cardiac pacemaker of Drosophila melanogaster responds to a range of neurotransmitters and hormones by adjusting heart rate. These cardioactive substances ultimately affect the activity of ion channels comprising the pacemaker. We report here work utilizing genetic variants and pharmacological tools to explore a subset of possible mechanisms for this cellular signaling, specifically: receptors, cAMP, cGMP, G proteins, and calcium. We found that alpha(1) adrenergic and 5-hydroxytryptamine(2) (5-HT(2)) receptors are critical components of mediating modulation of heart rate. There was no evidence that the cAMP system is part of the modulatory mechanism. cGMP is likely to be integral to one active pathway, as non-hydrolyzable forms of this cyclic nucleotide increase heart rate, and flies bearing the mutation sitter, a recessive allele of the foraging gene, which encodes a cGMP-dependent kinase, have tachycardia. Heart rhythm is affected by pertussis toxin and by agonists and antagonists of both alpha(1) adrenergic and 5-HT(2) receptors; this suggests involvement of two different types of G proteins. The l(4)16/ciD line, containing a mutation in CaM kinase II, eliminates pacemaker responsiveness to serotonin but is without effect on norepinephrine sensitivity. This result is the same as that for the CaM kinase II enzyme inhibitor KN-93. This work establishes a framework for further investigations into the control of the cardiac pacemaker, and expands the applicability of the Drosophila heart model.
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PMID:Modulation of the cardiac pacemaker of Drosophila: cellular mechanisms. 1191 4

We identified the isoforms of Ca(2+) /calmodulin-dependent protein kinase II (CaM kinase II) subunits in rat striatum. All four subunits of CaM kinase II alpha, beta, gamma and delta were detected including the isoforms of alphaB, gammaA, gammaA', gammaA.B, delta3 and delta7 with nuclear localization signal. We established NG108-15 cells with the stably expressed dopamine D2L receptor (D2LR, long form), which is an alternative splicing variant. The cells were termed NGD2L. Immunostaining demonstrated that D2LR was localized in plasma membranes. Calcium imaging with fluo-3 AM revealed that quinpirole, a D2R agonist, increased the intracellular Ca(2+), which was blocked by treatment with sulpiride and pertussis toxin in NGD2L cells, but not in mock cells. Furthermore, stimulation of D2LR with quinpirole in NGD2L cells activated the nuclear isoform of CaM kinase II. Stimulation of D2LR increased the expression of exon III- and IV-BDNF mRNA. Overexpression of CaM kinase II delta3 increased exon IV- but not exon III-BDNF mRNA. These results suggest that D2R is involved in the activation of the nuclear isoform of CaM kinase II and thereby in stimulation of gene expression through Ca(2+) signaling.
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PMID:Activation of nuclear Ca(2+)/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor gene expression by stimulation of dopamine D2 receptor in transfected NG108-15 cells. 1212 32