14.5 G Protein-Coupled Receptor & Receptor Kinase Signaling

G Protein-Coupled Receptors (GPCRs)

G protein-coupled receptors (GPCRs) constitute the largest and most pharmacologically targeted family of cell-surface receptors — roughly 800 human GPCRs, the targets of about one-third of all FDA-approved drugs. Structurally, every GPCR has a seven-transmembrane (7-TM) α-helical domain that snakes through the plasma membrane, with an extracellular N-terminus that contributes to ligand binding and an intracellular C-terminus that couples to the G protein. The PA-CAT Bulletin of Information, rev. 20240815 dedicates a G Protein-Coupled Receptor Signaling leaf to this family, and the G-protein cycle is the most-tested mechanism.

The Heterotrimeric G Protein Cycle

A GPCR is coupled to a heterotrimeric G protein composed of α, β, and γ subunits. In the resting state, Gα binds GDP and is complexed with Gβγ. The cycle proceeds:

1. Ligand binding to the GPCR induces a conformational change that lets the receptor act as a guanine nucleotide-exchange factor (GEF).
2. GDP release / GTP binding: Gα exchanges GDP for GTP, decreasing its affinity for Gβγ; Gα-GTP and Gβγ dissociate and can each regulate effectors.
3. Effector activation: Gα-GTP (and sometimes free Gβγ) modulates an effector enzyme or ion channel.
4. GTP hydrolysis: The intrinsic GTPase activity of Gα hydrolyzes GTP to GDP, returning Gα to the inactive state; it reassociates with Gβγ, terminating signaling.
5. Reset: The heterotrimer is ready for the next ligand-binding event.

The GTPase step is the built-in off switch. RGS proteins (regulators of G protein signaling) accelerate Gα GTPase activity, shortening the signal. Pathogens that disable this switch cause disease: cholera toxin ADP-ribosylates Gαs, locking it in the GTP-bound (active) state, producing uncontrolled cAMP in intestinal epithelium and massive secretory diarrhea; pertussis toxin ADP-ribosylates Gαi, preventing GDP release and blocking Gi inhibition of adenylyl cyclase.

Gα Families and Their Effectors

Different Gα isoforms couple to different effectors, producing distinct second-messenger responses — a high-yield PA-CAT table.

Note that a single ligand can engage different GPCRs in different tissues — acetylcholine acting through M1 (Gq) raises Ca²⁺ in smooth muscle, while the same neurotransmitter through M2 (Gi) lowers cAMP in cardiac pacemaker cells.

Receptor Tyrosine Kinases (RTKs)

Receptor tyrosine kinases are a different class of enzyme-linked cell-surface receptor, exemplified by the epidermal growth factor receptor (EGFR), insulin receptor, platelet-derived growth factor receptor (PDGFR), and HER2/ERBB2. RTKs transduce signals for growth, survival, differentiation, and metabolism, and their dysregulation is central to many cancers.

RTK Activation: Dimerization and Autophosphorylation

Most RTKs are single-pass transmembrane proteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Activation proceeds:

1. Ligand binding (e.g., EGF binding EGFR) induces receptor dimerization — two receptor monomers pair up.
2. Trans-autophosphorylation: Each kinase domain in the dimer phosphorylates specific tyrosines on the partner's cytoplasmic tail.
3. Docking-site creation: The phosphotyrosines serve as binding sites for SH2-domain and PTB-domain proteins, which assemble signaling complexes.
4. Downstream cascade activation: Adapter proteins such as Grb2 recruit SOS (a GEF), which loads Ras with GTP, launching the MAPK cascade.

The insulin receptor is an exception: it is already a preformed dimer (α₂β₂) held by disulfide bonds, and ligand binding induces trans-autophosphorylation without a dimerization step.

The Ras → Raf → MEK → ERK (MAPK) Cascade

The mitogen-activated protein kinase (MAPK) cascade is the canonical RTK signaling route and a textbook example of amplification.

Activated Ras-GTP recruits Raf to the membrane; Raf phosphorylates and activates MEK, which phosphorylates and activates ERK. ERK translocates to the nucleus and phosphorylates transcription factors that drive cell proliferation and differentiation. Each kinase in the cascade phosphorylates many downstream kinases, producing the amplification discussed in section 14.3.

Termination: Ras has intrinsic GTPase activity, accelerated by GAPs (GTPase-activating proteins) like NF1 (neurofibromin). Protein phosphatases dephosphorylate Raf, MEK, and ERK; receptor endocytosis and degradation also dampen signaling.

GPCR vs. RTK — Quick Comparison

Clinical Relevance

Both families are clinically rich. β-adrenergic antagonists (propranolol, metoprolol) block Gs-coupled β1/β2 receptors; antihistamines block Gi-coupled H1 receptors; opioids activate Gi-coupled μ-receptors, lowering neuronal cAMP. On the RTK side, trastuzumab (Herceptin) is a monoclonal antibody against HER2 in HER2-amplified breast cancer; erlotinib/gefitinib inhibit EGFR kinase activity in lung cancers with EGFR mutations; imatinib (Gleevec) targets the BCR-ABL tyrosine kinase in chronic myeloid leukemia. Cholera (Gαs locked on) and pertussis (Gαi locked off) anchor the infectious-disease link to G-protein signaling.

Why This Matters on the PA-CAT

This section completes the Signal Transduction group and is the most likely source of mechanism-heavy items. Expect tests of: (1) the Gα GDP/GTP cycle and what terminates the signal (intrinsic GTPase, accelerated by RGS), (2) which Gα family activates which effector (Gs↑cyclase, Gi↓cyclase, Gq→PLCβ), (3) the RTK activation sequence (ligand → dimerization → trans-autophosphorylation → SH2 docking), (4) the order of the MAPK cascade (Raf → MEK → ERK), and (5) clinical correlations: cholera toxin on Gαs, β-blockers on Gs, trastuzumab on HER2. Be ready to combine this with 14.3's second messengers and 14.4's intracellular receptors into an integrated view of how cells receive and process signals.