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Review
. 2015 Mar;65(3):203-10.
doi: 10.1097/FJC.0000000000000195.

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

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Free PMC article
Review

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

Alan V Smrcka. J Cardiovasc Pharmacol. .
Free PMC article

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, G protein-coupled receptors have been identified at the nuclear envelope implying intracellular localization of the signaling systems that respond to G protein-coupled receptors. 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.

Figures

Figure 1
Figure 1
Possible mechanisms for nuclear envelope scaffolded PLCε to access and hydrolyze PI4P found in the Golgi. A) An extended scaffold involving PLCε scaffolded to mAKAP, which is in turn scaffolded to nesprin-1α at the nuclear envelope may span the space between the outer nuclear envelope and the cis Golgi to hydrolyze PI4P in trans. B. Scaffolding of PLCε to mAKAP may bind PLCε in a way that allows dissociation and local action at the cis Golgi. Binding to of PLCε to mAKAP would serve to increase the local concentration of PLCε in the space between the NE and the cis Golgi. C. Phospholipid transfer proteins (PLTP) such as oxysterol binding protein (OSBP) have recently been shown to transport PI4P from the Golgi to the ER in exchange for cholesterol at Golgi-ER membrane contact sites. Since the NE is contiguous with the ER it is possible that this process could occur at the large Golgi-ER interface to supply PI4P to the NE where it could be accessed by mAKAP associated PLCε.
Figure 2
Figure 2
Scenarios for access to phosphoinositide substrates by PLCs downstream of GPCRs. A) GPCRs on the inner NE could activate PLCβ that could theoretically transiently dissociate to access PIP2 in the nuclear matrix. PIP2 has been found in the nuclear matrix. B) Similar to A but the PIP2 substrate would be present in the nuclear envelope. This would be a preferred substrate for a PLC activated on the nuclear envelope but the evidence for the presence of PIP2 at this location is lacking. C) As in Figure 1C, GPCR activated PLC on the outer nuclear envelope could access PI4P supplied to the nuclear envelope from the Golgi by PLTPs. D) PLCs activated by GPCRs on the outer nuclear envelope could transiently dissociate to access PI4P in the Golgi.

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