Lecture 14: Activation and Inhibition of Proteins – Quick Notes

Signal Transduction: Key Concepts

• Active receptor starts a chain of events; multi-step pathways coordinate the cellular response.
• Message transmitted via second messengers or phosphorylation.
• Receptors → relay proteins/second messengers → cellular response.

Two Core Mechanisms

• Second messengers: intracellular molecules change concentration after receptor activation; not membrane-bound; example: cAMP from adenylate cyclase, leading to downstream kinase activation.
• Phosphorylation cascade: kinases transfer phosphates from ATP to proteins; phosphatases remove phosphates; multiple kinases create a phosphorylation cascade.
• Basic chemical steps: $ATP \rightarrow ADP + P_i$ (kinase-catalyzed phosphorylation).

G-Protein Coupled Receptors (GPCRs)

• GPCRs use heterotrimeric G proteins to start signaling.
• G protein types and effects:
  • $G_{\alpha s}$ – stimulatory; activates adenylyl cyclase → ↑ $[cAMP]$ → PKA activation.
  • $G_{\alpha i}$ – inhibitory; decreases adenylyl cyclase activity → ↓ $[cAMP]$.
• The G protein cycle:
  • Inactive: $G<em>{\alpha\text{-GDP}} + G</em>{\beta\gamma}$
  • Receptor activation promotes GDP \rightarrow GTP exchange: $G<em>{\alpha\text{-GDP}} \rightarrow G</em>{\alpha\text{-GTP}}$
  • Active G(_{\alpha\text{-GTP}}) activates downstream effectors (e.g., adenylyl cyclase) → signal transduction
  • GTPase activity hydrolyzes GTP to GDP: $G<em>{\alpha\text{-GTP}} \xrightarrow{\text{GTPase}} G</em>{\alpha\text{-GDP}}$
  • Reassociation with G(\beta\gamma) forms inactive heterotrimer.
• Downstream readout often includes a second messenger like $[cAMP]$ and activation of kinases (e.g., PKA).

GPCR Examples

• Glucagon receptor (Gs-coupled): activation → G protein signaling → glycogen breakdown; also contributes to lipolysis.
• GLP-1 receptor (Gs-coupled): activation → insulin secretion from pancreatic beta cells.
• Therapeutic note (context): GLP-1 receptor agonists derived from peptide ligands (e.g., exendin-4/exenatide).

Receptor Tyrosine Kinases (RTKs)

• Activation sequence:
  • Ligand binding induces receptor conformation change → autophosphorylation on tyrosine residues.
  • Phosphorylated tyrosines recruit adaptor proteins which propagate signals.
• Key insulin receptor example (RTK):
  • Insulin binding leads to adaptor protein phosphorylation and signal relay, resulting in:
  • GLUT-4 translocation to the plasma membrane → increased glucose uptake in muscle/adipose tissue.
  • In liver, signaling promotes glycogen synthesis (glycogenesis).

Ligand-Gated Ion Channels

• Activation by ligand binding causes conformational change that opens an ion channel.
• No relay proteins required; ions flow directly, producing fast signaling.

Regulatory Features of Signal Transduction

• Receptor location determines where the effect occurs.
• Different cell types have distinct receptor and signaling molecule sets → different responses to the same ligand.
• Pathway branching and cross-talk coordinate signals across multiple pathways.

Key Definitions (At a Glance)

• Receptor: cellular protein (or complex) that controls signaling.
• Ligand: chemical that binds to a receptor.
• Agonist: ligand that activates the receptor.
• Antagonist: ligand that binds and prevents activation.

Quick Reference: Distinctions Among Receptor Classes

• Speed of signaling: $ext{Ligand-gated ion channels}$ > $ext{GPCRs}$ and $ext{RTKs}$ (ion channels are fastest; GPCRs and RTKs slower).
• GPCRs: use G proteins and second messengers (e.g., $[cAMP]$).
• RTKs: rely on receptor autophosphorylation and adaptor proteins.
• Ion channels: direct ion flow, fastest responses.