Dataset Information

G?_q and the Phospholipase C?3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.

ABSTRACT: Phospholipase C? (PLC?) enzymes are peripheral membrane proteins required for normal cardiovascular function. PLC? hydrolyzes phosphatidylinositol 4,5-bisphosphate, producing second messengers that increase intracellular Ca²⁺ level and activate protein kinase C. Under basal conditions, PLC? is autoinhibited by its C-terminal domains and by the X-Y linker, which contains a stretch of conserved acidic residues required for interfacial activation. Following stimulation of G protein-coupled receptors, the heterotrimeric G protein subunit G?_q allosterically activates PLC? and helps orient the activated complex at the membrane for efficient lipid hydrolysis. However, the molecular basis for how the PLC? X-Y linker, its C-terminal domains, G?_q, and the membrane coordinately regulate activity is not well understood. Using compressed lipid monolayers and atomic force microscopy, we found that a highly conserved acidic region of the X-Y linker is sufficient to regulate adsorption. Regulation of adsorption and activity by the X-Y linker also occurs independently of the C-terminal domains. We next investigated whether G?_q-dependent activation of PLC? altered interactions with the model membrane. G?_q increased PLC? adsorption in a manner that was independent of the PLC? regulatory elements and targeted adsorption to specific regions of the monolayer in the absence of the C-terminal domains. Thus, the mechanism of G?_q-dependent activation likely includes a spatial component.

SUBMITTER: Hudson BN

PROVIDER: S-EPMC7885793 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Gα<sub>q</sub> and the Phospholipase Cβ3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.

Hudson Brianna N BN Jessup Rachel E RE Prahalad Keshav K KK Lyon Angeline M AM

Biochemistry 20190730 32

Phospholipase Cβ (PLCβ) enzymes are peripheral membrane proteins required for normal cardiovascular function. PLCβ hydrolyzes phosphatidylinositol 4,5-bisphosphate, producing second messengers that increase intracellular Ca<sup>2+</sup> level and activate protein kinase C. Under basal conditions, PLCβ is autoinhibited by its C-terminal domains and by the X-Y linker, which contains a stretch of conserved acidic residues required for interfacial activation. Following stimulation of G protein-coupl ...[more]

PMID: 31322863

Similar Datasets

Project description:This study was conducted to test the hypothesis that the CYP1B1 (cytochrome P450 1B1)-testosterone metabolite 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension by promoting activation of group IV cPLA2α (cytosolic phospholipase A2α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomized cPLA2α+/+/Cyp1b1+/+ and cPLA2α-/-/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1-/- mice were infused with angiotensin II (700 ng/kg/min, subcutaneous) for 2 weeks and injected with 6β-hydroxytestosterone (15 μg/g/every third day, intraperitoneal). Systolic blood pressure was measured by tail-cuff and confirmed by radiotelemetry. Angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production were reduced by disruption of the cPLA2α or Cyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid to cPLA2α+/+/Cyp1b1+/+ mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II in cPLA2α+/+/Cyp1b1-/- mice but not in orchidectomized cPLA2α-/-/Cyp1b1+/+ mice, which were lowered by 5,8,11,14-eicosatetraynoic acid in cPLA2α+/+/Cyp1b1-/- mice. Antagonists of prostaglandin E2-EP1/EP3 receptors and thromboxane A2-TP receptors decreased the effect of 6β-hydroxytestosterone in restoring the angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production in cPLA2α+/+/Cyp1b1-/- mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA2α activation and generation of eicosanoids, most likely prostaglandin E2 and thromboxane A2 that exerts prohypertensive effects by stimulating EP1/EP3 and TP receptors, respectively. Therefore, agents that selectively block these receptors could be useful in treating testosterone exacerbated angiotensin II-induced hypertension and its pathogenesis.

Dataset Information

G?q and the Phospholipase C?3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.

Publications

Gα<sub>q</sub> and the Phospholipase Cβ3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

G?_q and the Phospholipase C?3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.