35. Although a majority of G protein-coupled receptors (GPCRs) act through adenylyl cyclase, many of them (GPCR) exert their effects by activating the plasma membrane-bound enzyme phospholipase C-β (PLC-β). These receptors activate the so-called inositolphospholipid signaling pathway mainly via a G protein called G_q, which activates PLC-β in much the same way that Gs activates adenylyl cyclase. Mentioned below are some Of the steps with functional characteristics of inositol phospholipid signaling pathway. one of which is not correct. Select the INCORRECT option.
(1) PLC-β acts on phosphatidyl inositol 4,5- biphosphate (PIP2), which is present in the inner half of the plasma membrane lipid bilayer. PLC-ß
(2) Activated PLC-β cleaves the PIP2 to generate two products: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).
(3) IP3 is a small lipid-soluble molecule that binds to IP3 receptor on plasma membrane thereby increasing Ca2+ concentration in the cytosol.
(4) DAG gets further cleaved to release arachidonic acid, which is used in the synthesis of eicosanoids including prostaglandins. DAG also activates Ca²⁺dependent protein kinase C or PKC.

 

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Introduction

The inositol phospholipid signaling pathway is a critical mechanism cells use to translate extracellular signals into intracellular responses. Often triggered by GPCRs coupled to the Gq protein, this pathway involves phospholipase C-β (PLC-β) acting on membrane phospholipids to generate two important second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Understanding this cascade clarifies how cells regulate calcium signaling, protein kinase C activation, and related cellular responses.

Overview of Steps

1. PLC-β and PIP2: PLC-β hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid located mainly in the inner leaflet of the plasma membrane, to yield IP3 and DAG.

2. Generation of Second Messengers: The cleavage of PIP2 produces IP3, a soluble signaling molecule, and DAG, a membrane-bound lipid.

3. IP3 Function: IP3 diffuses to the endoplasmic reticulum (ER), binding IP3 receptors that function as Ca2+ channels. This binding triggers the release of Ca2+ into the cytosol, initiating various calcium-dependent pathways.

4. DAG Function: DAG remains in the membrane and activates protein kinase C (PKC), which phosphorylates target proteins. Additionally, DAG can be further metabolized to release arachidonic acid, a precursor for eicosanoids like prostaglandins.

Identification of the Incorrect Statement

Let’s evaluate each given statement:

1. PLC-β acts on PIP2 located on the inner leaflet of the plasma membrane — This is correct; PIP2 is localized predominantly in the inner leaflet where PLC-β accesses it.

2. Activated PLC-β cleaves PIP2 into IP3 and DAG — This is also correct and fundamental to this signaling pathway.

3. IP3 is a small lipid-soluble molecule that binds IP3 receptor on plasma membrane increasing cytosolic Ca2+ — This is incorrect. IP3 is actually a water-soluble molecule and binds to IP3 receptors located on the endoplasmic reticulum (ER) membrane, not the plasma membrane. This binding releases Ca2+ from ER stores into the cytosol.

4. DAG gets cleaved to release arachidonic acid and activates Ca2+-dependent PKC — This is correct. DAG not only activates PKC but also can be converted to arachidonic acid, contributing to eicosanoid biosynthesis.

Conclusion

The inaccurate statement among the options is:

(3) IP3 is a small lipid-soluble molecule that binds to IP3 receptor on the plasma membrane thereby increasing Ca2+ concentration in the cytosol.

IP3 is water-soluble and acts on the ER membrane IP3 receptor.