Identification and Characterization of G Protein-Regulated Phospholipase C in Human Myocardium

Schnabel, Petra; Gäs, Heidi; Nohr, Theo; Camps, Montserrat; Böhm, Michael

doi:10.1006/jmcc.1996.0235

Cited by 24 publications

(12 citation statements)

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“…ID association for both proteins was recently also described by Jasnic-Savovic and colleagues 35 . Consistent with a previously reported interaction between CARP1 and phospholipase-C (PLC) 36 , we demonstrated in pull-down assays that the coiled coil region of PLCβ1, the main PLC isoform in hearts 37 , binds to both CARP1 and CARP2 ( Fig. 2e ).…”

Section: Resultssupporting

confidence: 91%

MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

et al. 2016

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MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure.

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Section: Resultssupporting

confidence: 91%

MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

et al. 2016

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“…Phospholipase C activity present in human myocardium has previously been shown to be regulated by heterotrimeric G proteins (Schnabel et al , 1996). In order to characterize the stimulation of myocardial PLC by G protein subunits in more detail, the effects of mastoparan, a tetradecapeptide from wasp venom, was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…As a control for the functionality of purified α t , PLC stimulation by purified exogenous βγ‐subunits was reversed by addition of a two fold excess of at (not shown). As shown in Table 4, neither GDP nor guanosine‐5′ O ‐(β‐thiodiphosphate) (GDPβS) were able to prevent mastoparan stimulation of myocardial PLC, although GDP has previously been shown to abolish G protein‐dependent stimulation by GTPγS (Schnabel et al , 1996). These results argue against the involvement of G proteins in the mediation of the mastoparan effect observed.…”

Section: Resultsmentioning

confidence: 99%

“…The pertussis toxin‐resistance of the effect provides indirect evidence against an involvement of βγ‐subunits as G i proteins are highly abundant in the human heart and could theoretically release enough βγ‐subunits to activate PLC. More direct evidence against a βγ‐mediated effect is provided by the control experiment showing that mastoparan stimulation is not abolished by addition of an excess of GDP‐bound α t , which is a well‐established scavenger of free βγ‐subunits (Camps et al , 1992a, b; Schnabel et al , 1996). A third line of evidence refuting the involvement of heterotrimeric G proteins in mastoparan stimulation of myocardial PLC is provided by the observation that the mastoparan effect is also present in the cytosolic fraction of human myocardium where G i and G q proteins are not present, as assessed by Western blotting (not shown).…”

Section: Discussionmentioning

confidence: 99%

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G protein‐independent stimulation of human myocardial phospholipase C by mastoparan

Schnabel

Gäs

Nohr

et al. 1997

British J Pharmacology

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1 Phosphoinositide-speci®c phospholipase C (PLC) is involved in the regulation of many cellular functions. In the myocardium, PLC-generated second messengers play a role in the regulation of contractile function and in the pathophysiology of myocardial hypertrophy. 2 In the present study, the eect of mastoparan, a tetradecapeptide which is capable of activating heterotrimeric G proteins by mimicking the action of an activated receptor, on membrane-bound human myocardial PLC, was investigated in a cell-free assay with exogenous phospholipids as a substrate. 3 Mastoparan stimulated human myocardial PLC approximately two fold with a half-maximal eect at approximately 2 mM and a maximal eect at 10 mM. The peptide did not alter the dependence of PLC on free calcium ions. In order to exclude non-speci®c eects of mastoparan due to its amphiphilic properties, dierent mastoparan derivatives were used as positive and negative controls. Mas17, an inactive mastoparan analogue with phsyical properties very similar to mastoparan, did not induce substantial PLC stimulation in human myocardial membranes. In contrast, Mas7, the most active mastoparan derivative known, caused a more pronounced PLC activation compared with the mother compound indicating that the eect was sequence-speci®c. Human myocardial PLC stimulation was pertussis toxin-insensitive and could not be abolished by addition of excess a-subunits from puri®ed retinal transducin or by excess GDP or GDPbS. In order to investigate whether mastoparan stimulated PLC via pertussis toxin-insensitive a q , a deletion mutant of PLCb 2 de®cient of the site of interaction with a q -subunits was expressed in COS-1 cells. Both wild-type and mutant PLCb 2 were similarly sensitive to stimulation by mastoparan. 4 It is concluded that mastoparan stimulates human myocardial PLC by a mechanism distinct from heterotrimeric G proteins.

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“…Although the ␦1 and ␥1-PLC isozymes seem to be predominant forms in normal cardiac cells [14,15], little is known about the expression and characteristics of PLC isozymes in myocardial ischemia. When PLC isozymes are activated in the ischemic heart, the initial products of PLC-mediated hydolysis of PIP 2 , IP 3 and DAG, may play pivotal roles as intracellular second messengers through the mobilization of calcium from intracellular stores and activation of protein kinase C, respectively.…”

Section: Introductionmentioning

confidence: 99%