20.1 G Protein-Coupled Receptors and Second Messengers

G protein-coupled receptors (GPCRs) are cell surface proteins that detect external signals and trigger internal responses. These receptors work with G proteins to activate enzymes that produce second messengers, amplifying the original signal and causing cellular changes.

Second messengers like cAMP, IP3, DAG, and calcium ions carry signals within cells, activating protein kinases and other effectors. This intricate system allows cells to respond to diverse stimuli, regulating processes from metabolism to gene expression.

GPCR Signaling Components

Structure and Function of GPCRs

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• G protein-coupled receptors (GPCRs) consist of seven transmembrane α-helices
• GPCRs detect extracellular signals through ligand binding
• Ligand binding induces conformational changes in GPCRs
• Activated GPCRs interact with G proteins on the intracellular side
• GPCRs can respond to diverse stimuli (hormones, neurotransmitters, light)

G Proteins and Their Activation

• G proteins comprise three subunits: α, β, and γ
• G proteins cycle between inactive (GDP-bound) and active (GTP-bound) states
• Activated GPCRs catalyze GDP-GTP exchange on the α subunit
• GTP binding causes dissociation of α subunit from βγ complex
• Both α-GTP and βγ can interact with downstream effectors

Effector Enzymes in GPCR Signaling

• Adenylyl cyclase catalyzes the conversion of ATP to cAMP
• Adenylyl cyclase can be stimulated or inhibited by different G protein α subunits
• Phospholipase C hydrolyzes membrane phospholipid PIP2
• Phospholipase C activation generates second messengers IP3 and DAG
• These effector enzymes amplify the initial signal from GPCR activation

Second Messengers

cAMP Signaling Pathway

• Cyclic AMP (cAMP) functions as a key intracellular second messenger
• cAMP is synthesized from ATP by adenylyl cyclase
• Increased cAMP levels activate protein kinase A (PKA)
• cAMP signaling regulates various cellular processes (metabolism, gene expression)
• Phosphodiesterases degrade cAMP, terminating the signal

Phospholipid-Derived Second Messengers

• Inositol trisphosphate (IP3) mobilizes calcium from intracellular stores
• IP3 binds to IP3 receptors on the endoplasmic reticulum
• Diacylglycerol (DAG) remains in the plasma membrane
• DAG activates protein kinase C (PKC)
• Both IP3 and DAG are produced by phospholipase C-mediated hydrolysis of PIP2

Calcium as a Second Messenger

• Calcium ions (Ca2+) serve as versatile intracellular signaling molecules
• Calcium signaling involves both influx from extracellular space and release from internal stores
• Calcium-binding proteins (calmodulin) mediate many calcium-dependent processes
• Calcium oscillations can encode information in their frequency and amplitude
• Calcium signaling regulates numerous cellular functions (muscle contraction, neurotransmitter release)

Downstream Effectors

Protein Kinase A Activation and Function

• Protein kinase A (PKA) exists as an inactive tetramer in the absence of cAMP
• cAMP binding to regulatory subunits releases active catalytic subunits
• PKA phosphorylates various target proteins on serine and threonine residues
• PKA regulates metabolic enzymes, ion channels, and transcription factors
• A-kinase anchoring proteins (AKAPs) localize PKA to specific cellular compartments

Protein Kinase C Activation and Targets

• Protein kinase C (PKC) requires both DAG and calcium for full activation
• PKC translocation to the plasma membrane occurs upon activation
• PKC phosphorylates numerous substrate proteins
• PKC regulates cell proliferation, differentiation, and apoptosis
• Multiple PKC isoforms exist with varying regulatory properties

Integration of Second Messenger Pathways

• Second messengers often work in concert to produce cellular responses
• Cross-talk between different signaling pathways can occur
• Spatial and temporal aspects of second messenger production influence signaling outcomes
• Scaffold proteins can organize signaling components into complexes
• Feedback mechanisms regulate the duration and intensity of second messenger signaling