GPCR: G-Protein Coupled Receptor & Signaling
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Signaling through G Protein-Coupled Receptors (GPCRs) involves a complex cascade of molecular events initiated by the binding of an extracellular ligand (such as hormones, neurotransmitters, or sensory stimuli) to the receptor. GPCRs are a large family of receptors with seven transmembrane domains, and they transmit signals through the activation of heterotrimeric G proteins.
In this case, we will focus on GPCR signaling through the Gs protein, which is a subtype of the G protein responsible for stimulating adenylyl cyclase, leading to the production of cyclic AMP (cAMP) as a second messenger.
Detailed Steps of Gs-Mediated GPCR Signaling (See Fgure):
Detailed Steps of Gs-Mediated GPCR Signaling (See Fgure):
Ligand Binding and Receptor Activation:
A ligand (such as adrenaline, glucagon, or dopamine) binds to the extracellular domain of the GPCR.
This binding induces a conformational change in the receptor, allowing it to interact with the intracellular heterotrimeric Gs protein.
2. Activation of G Protein:
In its inactive state, the Gs protein exists as a heterotrimer composed of Gαs, Gβ, and Gγ subunits, with GDP bound to the Gαs subunit.
Upon interaction with the activated GPCR, the Gαs subunit undergoes a conformational change, causing the exchange of GDP for GTP. This exchange activates the Gαs subunit.
The activated Gαs-GTP dissociates from the Gβγ dimer, and both Gαs-GTP and Gβγ can now interact with their respective effector proteins.
3. Activation of Adenylyl Cyclase:
The Gαs-GTP subunit interacts with and activates adenylyl cyclase, a membrane-bound enzyme.
Once activated, adenylyl cyclase catalyzes the conversion of ATP to cyclic AMP (cAMP), an important second messenger in this signaling pathway.
4. Elevation of cAMP Levels:
The production of cAMP leads to an increase in the intracellular concentration of this second messenger.
cAMP plays a critical role in regulating various cellular processes by acting as a signaling molecule that activates downstream effectors.
5. Activation of Protein Kinase A (PKA):
cAMP binds to the regulatory subunits of Protein Kinase A (PKA), causing them to dissociate from the catalytic subunits.
This releases the active catalytic subunits of PKA, which can now phosphorylate target proteins.
PKA phosphorylation of target proteins alters their activity, leading to various cellular responses, depending on the specific tissue and cell type.
6. Phosphorylation of Target Proteins:
Activated PKA phosphorylates a wide range of target proteins, including enzymes, ion channels, and transcription factors.
For example:
In the nucleus, PKA can phosphorylate CREB (cAMP response element-binding protein), a transcription factor that regulates gene expression by binding to the CRE (cAMP response element) in DNA (see Figure).
In the liver, PKA activates enzymes involved in glycogen breakdown (e.g., phosphorylase kinase) and inhibits enzymes involved in glycogen synthesis (e.g., glycogen synthase), promoting glucose release.
In cardiac cells, PKA phosphorylates calcium channels, increasing the strength and rate of heart contractions (a mechanism triggered by adrenaline).
Termination of Signal
Termination of the Signal:
The signal is terminated when the Gαs subunit hydrolyzes its bound GTP to GDP via its intrinsic GTPase activity, which is accelerated by RGS (Regulator of G protein Signaling) proteins.
Gαs-GDP reassociates with the Gβγ dimer, returning the Gs protein to its inactive state.
Adenylyl cyclase is no longer activated, and cAMP levels decrease as phosphodiesterases (PDEs) degrade cAMP into AMP.
PKA activity is downregulated as cAMP levels drop, causing the regulatory subunits of PKA to reassociate with the catalytic subunits, inactivating PKA.
Feedback and Desensitization:
Prolonged stimulation of GPCRs can lead to desensitization. This is often mediated by GPCR kinases (GRKs), which phosphorylate the activated receptor, promoting the binding of β-arrestins.
β-arrestins prevent further interaction between the GPCR and G proteins, effectively terminating the signal.
β-arrestins can also mediate receptor internalization through clathrin-mediated endocytosis, removing the receptor from the cell surface and recycling or degrading it.
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