negative regulation of phospholipase C-activating G protein-coupled receptor signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of phospholipase C-activating G protein-coupled receptor signaling pathway. [GOC:BHF, GOC:TermGenie]

Negative regulation of phospholipase C-activating G protein-coupled receptor signaling pathway involves a complex interplay of proteins and signaling molecules to dampen the activation of this important pathway. It is crucial for maintaining cellular homeostasis and preventing excessive signaling.

Here's a detailed breakdown of the process:

**1. Receptor Activation and G Protein Coupling:**
- The process begins with the activation of a G protein-coupled receptor (GPCR) that activates phospholipase C (PLC).
- Ligands bind to the GPCR, triggering a conformational change that allows it to interact with a heterotrimeric G protein, usually a Gq protein.

**2. G Protein Activation and PLC Stimulation:**
- Binding of the GPCR to the Gq protein activates it.
- The activated Gq protein releases its GDP and binds GTP.
- The activated G protein, specifically the Gα subunit, then interacts with and activates PLC.

**3. PLC Activation and IP3 Production:**
- PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol trisphosphate (IP3) and diacylglycerol (DAG).

**4. IP3-Mediated Calcium Release:**
- IP3 diffuses to the endoplasmic reticulum (ER) and binds to IP3 receptors.
- This binding triggers the release of calcium ions (Ca2+) from the ER into the cytoplasm.

**5. DAG-Mediated Protein Kinase C Activation:**
- DAG remains in the plasma membrane and activates protein kinase C (PKC).

**6. Calcium Signaling and Feedback Mechanisms:**
- The increased intracellular calcium concentration triggers various downstream signaling pathways.
- These pathways can lead to a variety of cellular responses, including muscle contraction, exocytosis, and gene expression.

**7. Negative Regulation Mechanisms:**
- Negative regulation mechanisms are essential to prevent overstimulation of the pathway and maintain cellular homeostasis.
- These mechanisms involve:
- **Desensitization of GPCRs:** The GPCR can become desensitized by phosphorylation and binding of arrestin proteins. This prevents further activation of the G protein.
- **Hydrolysis of GTP:** The GTP bound to the activated Gα subunit is hydrolyzed to GDP by GTPase-activating proteins (GAPs). This inactivates the Gα subunit and allows it to re-associate with the Gβγ subunit, terminating the signal.
- **Phosphatases:** Phosphatases dephosphorylate PLC and other signaling molecules, returning them to their inactive state.
- **Ca2+ Feedback Inhibition:** Increased intracellular calcium concentration can activate calcium-dependent phosphatases that negatively regulate PLC activity and other downstream signaling components.

**8. Cellular Consequences of Negative Regulation:**
- Negative regulation ensures that the signaling pathway is appropriately controlled, preventing excessive responses and maintaining cellular balance.
- Dysfunction in negative regulation can lead to various disorders, including hyperproliferative diseases, immune dysregulation, and neurodegenerative disorders.

**9. Examples of Negative Regulation Mechanisms:**
- The GPCR kinase (GRK) family of enzymes phosphorylates activated GPCRs, promoting their interaction with arrestin proteins and desensitizing the receptor.
- The RGS protein family acts as GAPs, accelerating the hydrolysis of GTP bound to the Gα subunit, effectively terminating the signaling cascade.
- Phospholipase Cβ (PLCβ) is negatively regulated by calcium-dependent phosphatases, such as calcineurin.

**10. Importance of Negative Regulation:**
- Maintaining the balance of PLC-activating GPCR signaling is essential for a wide range of physiological processes.
- Dysregulation of this pathway has been linked to various diseases, highlighting the importance of negative regulatory mechanisms in maintaining cellular health.

This detailed description provides a comprehensive understanding of the negative regulation of phospholipase C-activating G protein-coupled receptor signaling pathway. It encompasses the molecular mechanisms, feedback loops, and cellular consequences of this intricate regulatory process.'
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