Cell Signaling Principles
Focus on how cells communicate with one another.
Comprised of various mechanisms enabling cells to respond to internal and external cues.
Definition and Importance
All cells monitor their environment and respond:
Bacteria: Quorum sensing
Yeast: Mating processes
Multicellular organisms: Differentiation, immune responses, muscle contractions, etc.
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.
Example: Main pathways regulating fate/differentiation in CD4+ T cells.
Contact-Dependent: Requires physical interaction between signaling and target cells.
Paracrine: Local mediator signaling affecting nearby cells.
Synaptic: Fast communication through neurotransmitters across synapses.
Endocrine: Hormonal signaling via the bloodstream to distant target cells.
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).
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.
Types of Receptors
Ion-Channel-Coupled: Ligand-gated channels.
G-Protein-Coupled Receptors (GPCRs): Use heterotrimeric G proteins for signal relay.
Enzyme-Coupled Receptors: Act as enzymes or associate with activated enzymes (common: protein kinases).
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 Proteins: Enhance specificity and speed by organizing signaling complexes; can form pre-assembled or dynamic complexes upon receptor activation.
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 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.
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.
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.
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.
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.
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.
Phospholipase C Activation: Some G protein signals activate PLCβ, triggering the cascade:
Cleaves phosphatidylinositol to release second messengers IP3 and diacylglycerol.
Ubiquity: Calcium ions participate in many signaling pathways, allowing for dynamic responses through influx and OSCC over time.
Role of Calmodulin: Binds calcium and activates CaM kinases, integrating Ca2+ oscillations into cellular responses.
Examples: Heart muscle and olfactory receptors utilize G protein signaling to modulate ion channel activity, influencing action potentials.
NO Signaling: Mediates smooth muscle relaxation through diffusive signaling pathways, impacting blood vessel constriction.
Amplification and Desensitization: GPCR activation initiates pathways that significantly amplify initial signals but may lead to desensitization through receptor phosphorylation.