GPCR and RTK Signaling Flashcards

Overview of GPCRs
- GPCR: G-protein coupled receptors, play a crucial role in cellular signaling.
- Common elements: Signal molecule, receptor protein, inactive G protein.

Enzyme-Coupled Receptors
  - Examples:
    - Epidermal Growth Factor (EGF)
    - Transforming Growth Factor (TGF)
    - Insulin
    - Integrin
    - Fibroblast Growth Factor (FGF)
    - Cadherin/Wnt
    - Hippo
    - NF-kappa
  - Associated with roles in:
    - Development
    - Cancer
    - Tissue renewal and function
G-Protein-Coupled Receptors
  - Examples:
    - Serotonin
    - Dopamine
    - Acetylcholine
  - Often involved in:
    - Nervous system functions (senses, behavior)
    - Biological rhythms (sleep, reproduction)
Ion-Channel-Coupled Receptors
  - Roles include:
    - Enabling molecule transport across membranes
    - Control of H2O levels, membrane potential, ion concentrations
    - Impact on cellular functions like the cell cycle and muscle contraction

Activation and Inactivation of G-Proteins
- GEF (Guanine nucleotide Exchange Factor): Changes GDP to GTP, activating G-proteins.
- RGS (Regulators of G-protein Signaling): Reduces GTP to GDP, accelerating hydrolysis, thus inactivating the G-proteins.

Methods of Inactivation
  - GRK (GPCR kinase): Phosphorylates only activated receptors.
  - Arrestin: Binds to phosphorylated GPCRs, leading to receptor desensitization.
    - Functions:
      1. Inactivation of the receptor (prevents G-proteins from binding).
      2. Adaptor protein promoting receptor desensitization and internalization into vesicles for degradation.
        - Receptor recycling occurs in endosomes.

Three Major Signaling Pathways
  1. Adenylyl Cyclase (AC)
  2. Phospholipase C (PLC)
  3. Ion Channels

Process Overview
  - Step 1: Activation of GPCR leads to activation of the G-protein Gα subunit, which activates adenylyl cyclase.
  - Step 2: Adenylyl cyclase converts ATP into cyclic AMP (cAMP), a key secondary messenger.
  - Step 3: cAMP activates Protein Kinase A (PKA), leading to numerous downstream effects.
  - Step 4: Activated PKA translocates to the nucleus, phosphorylates CREB (cAMP response element-binding protein), leading to gene transcription.

Mechanism
  - Step 1: Activation of Gq
  - Step 2: Activated phospholipase C (PLC) splits PI(4,5)P into DAG and IP3.
  - Step 3: IP3 opens Ca2+ channels on the endoplasmic reticulum (ER).
  - Step 4: Ca2+ alongside DAG activates Protein Kinase C (PKC).
  - Outcome: This pathway increases cytosolic Ca2+, resulting in various cellular responses.

Calcium indicators can be used to visualize changes in local calcium concentrations through fluorescence changes.

Key Concepts
- RTKs serve as critical components in transmitting signals for growth, differentiation, and metabolism.
- Common RTKs include: EGF, insulin, FGF, and their associated signaling pathways.

Learning Objectives
  1. Explore signaling transduction pathways mediated by receptors.
  2. Identify molecular switches in cellular signaling.
  3. Understand mechanisms of RTK signaling.
Example of RTK Pathways:
  - Notch Signaling in Development:
    - Involves proteolytic cleavage and regulation of cellular processes such as proliferation and differentiation.
  - Signal Transduction Mechanisms:
  - RTKs undergo dimerization upon ligand binding, leading to autophosphorylation and activation of signaling pathways.

Types of Molecular Switches
  1. GTP-binding proteins: Activate by GTP-binding and deactivate by GDP; includes heterotrimeric G proteins and small monomeric G proteins.
  2. Phosphorylation: Significant in protein regulation shifts, involving kinases (add P) and phosphatases (remove P).
  3. Other Signaling Molecules: Second messengers that act through various modification processes.

Process
  1. Ligand binding triggers dimerization of monomeric RTK receptors.
  2. Trans-autophosphorylation activates the kinase domains.
  3. Formation of docking sites for intracellular signaling molecules.
Importance of Dimerization
- Dimerization aids in receptor activation, enhancing signaling propagation in response to extracellular stimuli.
- Pre-dimerization findings indicate a need for critical structural changes following ligand binding.