CBNS101 Lecture 08 Cell signaling principles, G protein coupled receptors

Fundamentals of Cell Biology

• Cell Signaling Principles

  • Focus on how cells communicate with one another.

  • Comprised of various mechanisms enabling cells to respond to internal and external cues.

Cell Signaling Overview

• Definition and Importance

  • All cells monitor their environment and respond:

    • Bacteria: Quorum sensing

    • Yeast: Mating processes

    • Multicellular organisms: Differentiation, immune responses, muscle contractions, etc.

Principles of Cell Signaling

• Mechanism of Interaction

  • Signal Molecules: Extracellular signals detected by receptors on cell surfaces.

  • Receptor Activation: Binding initiates a cascade of intracellular events involving signaling pathways.

  • Effector Proteins: End elements of pathways that perform cellular functions; about 1500 receptor proteins identified in the human genome.

Real World Application of Cell Signaling

• Example: Main pathways regulating fate/differentiation in CD4+ T cells.

Modes of Intercellular Signaling

1. Contact-Dependent: Requires physical interaction between signaling and target cells.

2. Paracrine: Local mediator signaling affecting nearby cells.

3. Synaptic: Fast communication through neurotransmitters across synapses.

4. Endocrine: Hormonal signaling via the bloodstream to distant target cells.

Characteristics of Cell Responses

• Specificity of Responses

  • Cells respond selectively to various signals (e.g., certain receptors expressed).

  • Survival often necessitates signaling; absence may trigger programmed cell death.

  • Integration of signals dictates cellular outcomes (responses vary according to cell type).

Types of Signals and Receptors

• Signal Characteristics

  • Signals may be water-soluble or insoluble, including:

    • Proteins/Peptides: e.g., growth factors.

    • Small Molecules: e.g., amino acids, steroids.

    • Gases: e.g., nitric oxide.

• Receptor Types

  • Most are transmembrane proteins binding to solubles; others are intracellular for hydrophobic signals.

Major Classes of Cell-Surface Receptors

• Types of Receptors

  1. Ion-Channel-Coupled: Ligand-gated channels.

  2. G-Protein-Coupled Receptors (GPCRs): Use heterotrimeric G proteins for signal relay.

  3. Enzyme-Coupled Receptors: Act as enzymes or associate with activated enzymes (common: protein kinases).

Intracellular Signaling Mechanisms

• Second Messengers: e.g., cyclic AMP, calcium ions, relayed signals across pathways.

• Molecular Switches: Alternate between active/inactive states via phosphorylation/dephosphorylation.

• GTPases: Cycle between GTP-bound (active) and GDP-bound (inactive) states.

Scaffolding in Signaling

• Scaffolding Proteins: Enhance specificity and speed by organizing signaling complexes; can form pre-assembled or dynamic complexes upon receptor activation.

Interaction Domains in Signaling Proteins

• Modularity: Signaling proteins possess small conserved interaction domains to form complexes:

  • SH2 & PTB: Bind phosphorylated tyrosines.

  • SH3: Binds proline-rich sequences.

  • PH: Binds phosphoinositides (PIPs).

Signal Integration and Properties

• Signal Processing: Combining multiple sources for coordinated responses; components can also activate or suppress downstream activities.

• Response Dynamics: Altered based on feedback loops, either amplifying or dampening responses to stimuli.

Feedback Mechanisms

• Positive Feedback: Produces a sharper and persistent response; can lead to stable, long-term changes like cell differentiation.

• Negative Feedback: Causes oscillations or dampened responses, allowing for adaptation to signals over time.

Summary of Cellular Signaling

• Cells integrate a set of extracellular signals via surface receptors, leading to activation of signaling cascades.

• Phosphorylation often modulates signaling proteins; the formation of complexes influences signaling pathways' efficacy.

• Feedback mechanisms regulate the intensity and duration of responses to maintain homeostasis.

G-Protein-Coupled Receptors (GPCRs)

• Overview: Largest family of cell-surface receptors (over 800 GPCRs in humans).

• Ligand Recognition: Involved in sensing hormones, neurotransmitters, and sensory signals (e.g., taste).

• Structure: Characterized by a common 7-transmembrane alpha-helical structure.

Mechanism of G-Protein Activation

• Subunit Composition: Heterotrimeric (α, β, γ) anchored to the membrane; activated upon ligand binding.

• GTP Hydrolysis: Activation of G proteins via GTP exchange, followed by dissociation for downstream signaling.

Signaling through Cyclic AMP

• Role of cAMP: Second messenger involved in various pathways; produced from ATP by adenylyl cyclase.

• PKA Activation: cAMP activates protein kinase A to phosphorylate target proteins, influencing gene expression.

Phosphatidylinositol Signaling

• Phospholipase C Activation: Some G protein signals activate PLCβ, triggering the cascade:

  • Cleaves phosphatidylinositol to release second messengers IP3 and diacylglycerol.

Calcium as a Second Messenger

• Ubiquity: Calcium ions participate in many signaling pathways, allowing for dynamic responses through influx and OSCC over time.

Calmodulin and Calcium Kinases

• Role of Calmodulin: Binds calcium and activates CaM kinases, integrating Ca2+ oscillations into cellular responses.

Ion Channel Regulation by G Proteins

• Examples: Heart muscle and olfactory receptors utilize G protein signaling to modulate ion channel activity, influencing action potentials.

Nitric Oxide (NO) and Cell Signaling

• NO Signaling: Mediates smooth muscle relaxation through diffusive signaling pathways, impacting blood vessel constriction.

GPCR Pathway Properties

• Amplification and Desensitization: GPCR activation initiates pathways that significantly amplify initial signals but may lead to desensitization through receptor phosphorylation.