Regulation of Phosphatidylinositol-specific Phospholipase C at the Nuclear Envelope in Cardiac Myocytes

Abstract

Phosphatidylinositol 4,5 bisphosphate hydrolysis at the plasma membrane by phospholipase C is one of the major hormone regulated intracellular signaling systems. The system generates the diffusible second messenger IP3 and the membrane bound messenger diacylglycerol. Spatial regulation of this system has been thought to be through specific subcellular distributions of the IP3 receptor or PKC. As is becoming increasingly apparent, receptor-stimulated signaling systems are also found at intracellular membranes. As discussed in this issue, GPCRs have been identified at the nuclear envelope implying intracellular localization of the signaling systems that respond to GPCRs. Here we discuss the evidence for the existence of PLC signals that regulate nuclear processes, as well as the evidence for nuclear and nuclear envelope localization of PLC signaling components, and their implications for cardiac physiology and disease.

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

“…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).…”

Adult Stem Cell Membrane Markers: Their Importance and Critical Role in Their Proliferation and Differentiation Potentials

“…Ca 2+ forms a complex with the protein calmodulin which regulates the activity of many proteins including various transcription factors [46,47]. Diacylglycerol is a glyceride of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages and it remains within the plasma membrane where it regulates the protein kinase signaling cascades through protein kinase C (PKC) activation [48].…”

Lipids contribute to epigenetic control via chromatin structure and functions

“…However, there are not likely to be many other farnesylated proteins, as the CaaX motif is present on few other proteins in the nuclear envelope proteome. Nonetheless, inositol triphosphate signaling has been clearly found in the nuclear envelope [41,42] and probably many more classes of lipid signaling species will be found when the nuclear envelope lipidome is finally directly investigated.…”