Phospholipase D regulates calcium oscillation frequency and nuclear factor-kappaB activity in histamine- stimulated

Qinghua Hu1, Viswanathan Natarajan, Roy C Ziegelstein

  • 1Department of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224-2780, USA. quinghuaa@welch.jhmi.edu

Histamine stimulates [Ca(2+)](i) oscillations in human aortic endothelial cells (HAEC), the frequency of which regulates the activity of nuclear factor-kappaB (NF-kappaB). This study was performed to determine whether phospholipase D (PLD) is involved in this signaling pathway. At a concentration of 1 microM, which stimulates [Ca(2+)](i) oscillations in this cell type, histamine initiated a twofold increase in [(32)P]phosphatidybutanol (PBt), an index of PLD activity as early as 5 min after stimulation. During established [Ca(2+)](i) oscillations induced by 1 microM histamine, 0.3% n-butanol, which "functionally" redirects phosphatidic acid formed by PLD to PBt, decreased [Ca(2+)](i) oscillation frequency by approximately 50% and produced a similar reduction in NF-kappaB activity. In the presence of the inositol 1,4,5-trisphosphate receptor blocker xestospongin C, which itself decreases the frequency of histamine-stimulated [Ca(2+)](i) oscillations, n-butanol produced a further decrease in oscillation frequency that was not associated with an additional reduction in NF-kappaB activity. This study shows that activation of PLD by histamine regulates [Ca(2+)](i) oscillation frequency and NF-kappaB activity in HAEC.

Related Concept Videos

Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Amplifying Signals via Second Messengers01:15

Amplifying Signals via Second Messengers

Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
Feedback Regulation of Calcium Concentration01:27

Feedback Regulation of Calcium Concentration

Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...