Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identified dexamethasone-induced Ras protein 1 (Dexras1) as a negative regulator of protein kinase C (PKC) delta, and the consequences of this regulation have been examined for adenylyl cyclase (EC 4.6.1.1) type 2 (AC2) signaling. Dexras1 expression in human embryonic kidney 293 cells completely abolished dopamine D2 receptor-mediated potentiation of AC2 activity, which is consistent with previous reports of its ability to block receptor-mediated Gbetagamma signaling pathways. In addition, Dexras1 significantly reduced phorbol 12-myristate 13-acetate (PMA)-stimulated AC2 activity but did not alter Galpha(s)-mediated cAMP accumulation. Dexras1 seemed to inhibit PMA stimulation of AC2 by interfering with PKCdelta autophosphorylation. This effect was selective for the delta isoform because Dexras1 did not alter autophosphorylation of PKCalpha or PKCepsilon. Dexras1 disruption of PKCdelta autophosphorylation resulted in a significant blockade of PKC kinase activity as measured by [gamma-32P]ATP incorporation using a PKC-specific substrate. Moreover, Dexras1 and PKCdelta coimmunoprecipitated from whole-cell lysates. Dexras1 did not alter the membrane translocation of PKCdelta; however, the ability of Dexras1 to interfere with PKCdelta autophosphorylation was isoprenylation-dependent as determined using the farnesyltransferase inhibitor methyl {N-[2-phenyl-4-N [2(R)-amino-3-mecaptopropylamino] benzoyl]}-methionate (FTI-277) and a CAAX box-deficient Dexras1 (C277S) mutant. PMA-stimulated AC2 activity was also not affected by Dexras1 C277S. Taken as a whole, these data suggest that Dexras1 functionally interacts with PKCdelta at the cellular membrane through an isoprenylation-dependent mechanism to negatively regulate PKCdelta activity. Moreover our study suggests that Dexras1 acts to modulate the activation of AC2 in an indirect fashion by inhibiting both Gbetagamma- and PKC-stimulated AC2 activity. The current study provides a novel role for Dexras1 in signal transduction.
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PMID:Dexamethasone-induced Ras protein 1 negatively regulates protein kinase C delta: implications for adenylyl cyclase 2 signaling. 1648 24

Parkinson's disease (PD) is characterized by a selective loss of dopamine-producing neurons in the substantia nigra (SN), which in turn results in dopamine depletion in the striatum, and the presence of neuronal cytoplasmic inclusions known as Lewy bodies (LBs). Alpha-synuclein is a presynaptic protein that accumulates abnormally in LBs and is seen predominantly in cases of dementia with LBs. Although the central role of alpha-synuclein in neurodegeneration has been previously demonstrated by the discovery of missense alpha-synuclein mutations in familial PD, the specific mechanism by which alpha-synuclein contributes to these diseases remains unclear. In the present study, we examined whether alpha-synuclein affects the downstream signaling of dopamine D2 receptor (D2R). In CHO cells stably transfected with D2Rs, alpha-synuclein enhanced dopamine D2-agonist-mediated inhibition of adenylate cyclase, which consequently affected its downstream cAMP-responsive element (CRE)-mediated gene transcription, while C-terminal deletion mutant of alpha-synuclein did not. Our study suggests that the alpha-synuclein enhances the dopamine-mediated intracellular signaling pathways by D2R, thus provide a possible mechanism in presynaptic regulation of the synaptic homeostasis in the dopaminergic neurotransmission.
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PMID:Alpha-synuclein enhances dopamine D2 receptor signaling. 1708 19


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