Role of phospholipase Cε in physiological phosphoinositide signaling networks

Abstract

Receptor-initiated phospholipase C activation and generation of IP(3) and DAG are important common triggers for a diversity of signal transduction processes in many cell types. Contributing to this diversity is the existence and differential cellular and subcellular distribution of distinct phospholipase C isoforms with distinct regulatory properties. The recently identified PLCε enzyme is an isoform that is uniquely regulated by multiple upstream signals including ras-family GTP binding proteins as well as heterotrimeric G-proteins. In this review we will consider the well documented biochemical regulation of this isoform in the context of cell and whole animal physiology and in the context of other G protein-regulated PLC isoforms. These studies together reveal a surprisingly wide range of unexpected functions for PLCε in cellular signaling, physiology and disease.

Fig. 1

Phospholipase C isoforms. A) Reaction catalyzed by PI-PLC and overall structure. Structure of PLCβ2 (Protein Database ID: 2ZKM) taken from [29] and rendered with Molsoft ICM. The catalytic domain comprised the X and Y domains is in red, the Pleckstrin Homology (PH) domain is in blue, the EF hand domain is in yellow and the C2 domain is in purple. B) PLC isoforms with domains color coded as in panel A. C) Two splice variants of PLCε which include in addition to the aforementioned common domains, 2 ras association ho- mology (RA) domains and a CDC25 homology guanine nucleotide exchange factor (GEF) domain.

Fig. 2

Common mechanisms for PLCε regulation of CICR in cardiac myocytes and pancreatic β cells downstream of Gs-coupled receptors. A) Common upstream components regulate of PLCε by Gs coupled receptors in adult cardiac myocytes and isolated pancreatic β cells [19,54]. B) Signaling downstream of PLCε. In red are components found to be involved in regulation of CICR in both cardiac myocytes and pancreatic β cells [19,54]. An alternative pathway has also been proposed and is depicted in black and may operate in β cells as well [57].

Fig. 3

PLCε scaffolding in cardiac myocytes. PLCε is scaffolded at different subcellular loca- tions to perform distinct functions. PLCε scaffolded to RyR2 in the sarcoplasmic reticulum (SR) functions in CICR; PLCε scaffolded to mAKAP at the nuclear (Nuc) envelope is involved in hypertrophy. Additional roles for PLCε at the plasma membrane PM may also exist.