The atypical ‘b’ splice variant of phospholipase Cβ1 promotes cardiac contractile dysfunction

Grubb, David R.; Crook, Bryony; Ma, Yi; Luo, Jieting; Huang, Qian; Gao, Xiao‐Ming; Kiriazis, Helen; Du, Xiao‐Jun; Gregorevic, Paul; Woodcock, Elizabeth A.

doi:10.1016/j.yjmcc.2015.04.016

Cited by 11 publications

(25 citation statements)

References 54 publications

(84 reference statements)

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“…Phospholipase C (PLC) 2 enzymes hydrolyze phosphatidylinositol lipids at cell membranes, producing inositol phosphates and diacylglycerol, which in turn promote the release of Ca 2ϩ from intracellular stores and activate protein kinase C (PKC) (1). Of the six PLC subfamilies, PLC␤ and PLC⑀ are required for normal cardiovascular function, and dysregulation of their expression and/or activity can result in cardiac hypertrophy and heart failure (2)(3)(4)(5)(6). The activity of these lipases is autoinhibited by various domains and structural elements but can be stimulated up to ϳ60-fold following activation of cell surface receptors (1).…”

mentioning

confidence: 99%

Direct observation of conformational dynamics of the PH domain in phospholipases Cɛ and β may contribute to subfamily-specific roles in regulation

Garland‐Kuntz¹,

Vago

Sieng³

et al. 2018

Journal of Biological Chemistry

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Phospholipase C (PLC) enzymes hydrolyze phosphatidylinositol lipids to produce second messengers, including inositol‐1,4,5‐triphosphate (IP3) and diacylgycerol (DAG), which increase intracellular calcium and activate protein kinase C (PKC), respectively. PLCɛ contributes to cardiac hypertrophy and contractility, as well as to oncogenic and inflammatory signaling pathways following activation of G protein‐coupled receptors and receptor tyrosine kinases. PLCɛ shares a conserved core with the PLC superfamily, but the roles of individual domains in regulation of activity and membrane binding have not been established. We used functional assays to show that the PLCɛ PH domain significantly increases basal lipase activity, but is dispensable for stability. We provide the first structural insights into domain organization of PLCɛ using small‐angle X‐ray scattering (SAXS) and electron microscopy (EM) to reveal that the PH domain is conformationally heterogeneous in solution. Comparisons of the PLCɛ solution structure to that of the closely‐related PLCβ enzyme demonstrate that the PLCβ PH domain is also mobile in solution, in contrast to previously reported crystal structures. We propose that the dynamic nature of the PLC PH domain and resulting conformational heterogeneity contributes to subfamily‐specific differences in activity and regulation by G proteins. We are now using cryo‐EM to expand on these findings and obtain higher resolution structures. Support or Funding Information This work is supported by the Purdue Center for Cancer Research, AHA grant 16SDG29930017, NIH NLHBI 1R01HL141076‐01 to A.M.L., and Purdue College of Science Staff and Administrative & Professional Staff Advisory Council Professional Development awards to E.E.G. SAXS experiments used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE‐AC02‐06CH11357. This project was supported by grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the National Institutes of Health. Use of the Pilatus 3 1M detector was provided by grant 1S10OD018090‐01 from NIGMS. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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confidence: 99%

Direct observation of conformational dynamics of the PH domain in phospholipases Cɛ and β may contribute to subfamily-specific roles in regulation

Garland‐Kuntz¹,

Vago

Sieng³

et al. 2018

Journal of Biological Chemistry

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“…to the nucleus, which might suggest that G q -receptor signaling at the sarcolemma is pathologic, which is supported by studies with AT-Rs (31,32). In support of this concept, adenoviral mediated expression of the PLC␤1b at the sarcolemma induces contractile dysfunction (44). In summary, our hypothetical model of compartmentalized G q -receptor signaling, where nuclear G q -receptor signaling is cardioprotective, suggests a more nuanced view of G q -receptor function in cardiac myocytes.…”

Section: Compartmentalized Myocyte G Q -Receptor Signalingmentioning

confidence: 54%

Subcellular compartmentalization of proximal Gαq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes

Dahl

Healy

et al. 2018

Journal of Biological Chemistry

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G protein-coupled receptors that signal through Gα (G receptors), such as α-adrenergic receptors (α-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cβ1 (PLCβ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP) to produce inositol 1,4,5-trisphosphate (IP) and diacylglycerol. Despite these common proximal signaling mechanisms, G receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, G receptors are thought to induce myocyte hypertrophy through a mechanism termed excitation-transcription coupling, which provides a mechanistic basis for compartmentalization of calcium required for contraction IP-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of G-receptor signaling as a mechanistic basis for unique G receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that α-ARs co-localize with PLCβ1 and PIP at the nuclear membrane. Further, nuclear α-ARs induced intranuclear PLCβ1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response ( significant up- or down-regulation of 806 genes). Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLCβ1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of α-AR-induced transcription. In summary, these results link G-receptor compartmentalization in cardiac myocytes to unique hypertrophic transcription. They suggest a new model of excitation-transcription coupling in adult cardiac myocytes that accounts for differential G-receptor localization and better explains distinct physiological functions of G receptors.

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“…Failed myocardium from humans and experimental animals showed heightened expression and activity of phospholipase Cβ1b (PLCβ1b) [ 11 ], one of the splice variants of PLCβ1 [ 12 ] that initiates signaling responses downstream of Gq-coupled receptor activation [ 13 ]. Our studies showed that increasing PLCβ1b expression in adult mouse hearts by viral transduction was sufficient to cause rapidly developing, sustained contractile dysfunction [ 14 ], which lasted for several months in the absence of other pathological changes in the myocardium [ 14 ] (time course depicted diagrammatically in Fig 1 ). Further evidence pointing to the significance of the contribution of heightened PLCβ1b to pathology was provided by a more recent study [ 15 ], which showed that inhibiting PLCβ1b selectively prevented or reversed contractile dysfunction following pressure overload induced by trans-aortic constriction.…”

Section: Introductionmentioning

confidence: 99%

“…D . Diagram showing the time frame of changes in function in relation to the 8 week time point used in the current study [ 14 ]. E .…”

Section: Introductionmentioning

confidence: 99%

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Chronic Contractile Dysfunction without Hypertrophy Does Not Provoke a Compensatory Transcriptional Response in Mouse Hearts

et al. 2016

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Diseased myocardium from humans and experimental animal models shows heightened expression and activity of a specific subtype of phospholipase C (PLC), the splice variant PLCβ1b. Previous studies from our group showed that increasing PLCβ1b expression in adult mouse hearts by viral transduction was sufficient to cause sustained contractile dysfunction of rapid onset, which was maintained indefinitely in the absence of other pathological changes in the myocardium. We hypothesized that impaired contractility alone would be sufficient to induce a compensatory transcriptional response. Unbiased, comprehensive mRNA-sequencing was performed on 6 biological replicates of rAAV6-treated blank, PLCβ1b and PLCβ1a (closely related but inactive splice variant) hearts 8 weeks after injection, when reduced contractility was manifest in PLCβ1b hearts without evidence of induced hypertrophy. Expression of PLCβ1b resulted in expression changes in only 9 genes at FDR<0.1 when compared with control and these genes appeared unrelated to contractility. Importantly, PLCβ1a caused similar mild expression changes to PLCβ1b, despite a complete lack of effect of this isoform on cardiac contractility. We conclude that contractile depression caused by PLCβ1b activation is largely independent of changes in the transcriptome, and thus that lowered contractility is not sufficient in itself to provoke measurable transcriptomic alterations. In addition, our data stress the importance of a stringent control group to filter out transcriptional changes unrelated to cardiac function.

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The atypical ‘b’ splice variant of phospholipase Cβ1 promotes cardiac contractile dysfunction

Cited by 11 publications

References 54 publications

Direct observation of conformational dynamics of the PH domain in phospholipases Cɛ and β may contribute to subfamily-specific roles in regulation

Direct observation of conformational dynamics of the PH domain in phospholipases Cɛ and β may contribute to subfamily-specific roles in regulation

Subcellular compartmentalization of proximal Gαq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes

Chronic Contractile Dysfunction without Hypertrophy Does Not Provoke a Compensatory Transcriptional Response in Mouse Hearts

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