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.

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