PCB 3023 Chapter 16 Review: Cell Communication

Cell Communication

Four Basic Types of Cell Signaling

  • Endocrine:
    • Signaling molecules (hormones) are transported through the bloodstream.
    • Generalized signaling affecting targets throughout the body.
    • Soluble signal.
  • Paracrine:
    • Signaling via local mediators that affect cells in the vicinity.
    • Signaling molecules do not travel through the bloodstream.
    • Soluble signal.
  • Neuronal:
    • Signaling via neurotransmitters.
    • Involves two components: long-distance delivery but directed to specific targets.
    • Soluble signal.
  • Contact-dependent:
    • Signaling occurs through direct cell-cell contact.
    • Signal is membrane-bound.

Signal Specificity

  • Cells respond to signaling molecules based on their receptors.
  • Receptors are proteins that bind specific signal molecules.
  • Receptors can be located in the plasma membrane, cytosol, or nucleus.

Signal Effects and Combinations

  • A single signal can cause multiple effects in a cell through amplification and branching of intracellular signals.
  • One signal can modify the effects of another.
  • Different cells respond to different sets of signals based on their receptors.
  • The combined signals determine cell behavior (survival, division, differentiation, or death).

Adrenaline Example

  • Adrenaline (epinephrine) is released from the adrenal glands and affects cells throughout the body with adrenergic receptors.
  • Adrenergic receptors are G protein-linked receptors that activate cAMP production.
  • cAMP leads to:
    • Increased heart rate.
    • Glycogen breakdown in skeletal muscle.
    • Triglyceride breakdown in fat cells.
  • The same signal (adrenaline) can produce different effects in different cells due to variations in intracellular signaling molecules and effector proteins.

Types of Extracellular Signal Molecules

  • Hydrophilic:
    • Bind to cell surface receptors.
  • Hydrophobic:
    • Bind to intracellular receptors.

Molecular Switches

  • Proteins act as molecular switches in signal transduction.
  • Phosphorylation:
    • Protein kinases add phosphate groups (from ATP) to signaling proteins, activating or inactivating them.
    • Protein phosphatases remove phosphate groups, reversing the effect.
    • ATP{ATP}
  • GTP-binding proteins:
    • Activated when they bind GTP, exchanging GDP for GTP.
    • Inactivated when they hydrolyze GTP to GDP.

Second Messengers

  • Cells rapidly produce intracellular second messengers using enzymes.
  • Examples:
    • Adenylyl cyclase: converts ATP to cyclic AMP (cAMP).
    • Phospholipase C: cleaves inositol phospholipid to produce IP3 and DAG.

Cyclic AMP (cAMP)

  • Synthesized by adenylyl cyclase.
  • Degraded by cyclic AMP phosphodiesterase, which breaks the bond forming AMP.
  • Formed from ATP in a cyclization reaction that removes two phosphate groups and joins the remaining phosphate group to the sugar part of the AMP molecule.

Inositol Phospholipid, IP3, and DAG

  • Phospholipase C cleaves inositol phospholipid (in the cytosolic leaflet of the membrane lipid bilayer) into IP3 and DAG.
  • IP3 (inositol 1,4,5-trisphosphate):
    • A small, water-soluble intracellular signaling molecule.
    • Triggers the release of Ca2+{Ca^{2+}}
    • from the endoplasmic reticulum (ER) into the cytosol.
  • DAG (diacylglycerol):
    • A small messenger molecule that helps activate protein kinase C (PKC).

Cytosolic Calcium Concentration

  • IP3 binds to and opens Ca2+{Ca^{2+}}
    channels in the ER membrane.
  • Ca2+{Ca^{2+}}
    rushes out of the ER into the cytosol, increasing Ca2+{Ca^{2+}}
    concentration.

Cell Surface Receptors

  1. Enzyme-coupled receptors
  2. G protein-coupled receptors (GPCRs)
  3. Ion channel-coupled receptors

G Protein-Linked Receptors

  • Structure:
    • 7-pass transmembrane protein.
  • G Proteins:
    • Contain three subunits: alpha (α), beta (β), and gamma (γ).
    • About 20 different types of G proteins.
    • Alpha and gamma subunits are tethered to the plasma membrane by lipid tails.
  • Signal Transduction Steps:
    1. Ligand binds to the receptor, causing a conformational change.
    2. G protein binds to the receptor via the alpha subunit, causing a conformational change.
    3. Alpha subunit binds GTP, causing a conformational change.
    4. Alpha subunit dissociates from the beta-gamma (βγ) complex, activating the G protein.
  • Duration of Signal:
    • Controlled by the alpha subunit's intrinsic GTPase activity.
    • The alpha subunit hydrolyzes GTP to GDP, returning the G protein to its inactive conformation.

GPCR and Heart Rate

  • Acetylcholine released by nerves binds to GPCRs on heart pacemaker cells.
  • The beta-gamma complex binds to and opens K+ channels in the plasma membrane.
  • Opening K+ channels increases the membrane's permeability to K+, making it more difficult to electrically activate and slowing down the heart rate by hyperpolarizing the membrane.

GPCR and Protein Kinase A (PKA)

  • Ligand binding to a GPCR activates the alpha subunit of the G protein and adenylyl cyclase.
  • Adenylyl cyclase increases the synthesis of cyclic AMP (cAMP) from ATP.
  • cAMP activates protein kinase A (PKA).
  • PKA phosphorylates:
    • Enzymes (turning them on or off).
    • Gene regulatory proteins.
  • Example:
    • Epinephrine (adrenaline) operates through this system.

GPCR and Protein Kinase C (PKC)

  • Both the alpha subunit and the beta-gamma complex activate phospholipase C.
  • Phospholipase C hydrolyzes a membrane inositol phospholipid, producing IP3 and DAG.
  • IP3 diffuses through the cytosol and triggers Ca2+{Ca^{2+}}
    release from the ER.
  • DAG remains in the plasma membrane and, together with Ca2+{Ca^{2+}}
    , helps activate protein kinase C (PKC).
  • PKC phosphorylates intracellular proteins, propagating the signal.

Protein-Protein Interactions

  • At least three protein-protein interactions occur when a ligand binds to a GPCR and sends a signal to the nucleus:
    • Ligand-receptor interaction
    • Receptor-G protein interaction
    • G protein subunit-effector interaction

Enzyme-Linked Receptors

  • Structure:
    • Binding of an extracellular signal molecule causes two receptor molecules to dimerize.
    • Dimerization brings the intracellular tails of the receptors together, activating their kinase domains.
    • Kinase domains phosphorylate tyrosine residues on the adjacent receptor tail.
  • Signal Transduction:
    • Phosphorylated tyrosine residues serve as docking sites for intracellular signaling proteins with specialized interaction domains.
  • Effects in Target Cells:
    • Cell growth
    • Proliferation
    • Differentiation
  • Disease:
    • Defects in enzyme-linked receptor signaling can lead to cancer.
    • 30% of cancers have mutations in the Ras gene, making it hyperactive.

Receptor Tyrosine Kinases (RTKs) and Ras/MAP Kinase Pathway

  • Activated RTKs recruit many proteins, including Ras.
  • Ras is a monomeric GTP-binding protein.
  • Similarities between Ras and G proteins:
    • Both act as molecular switches regulating cellular signaling.
    • Both are active when GTP is bound and inactive when GDP is bound.
  • Differences between Ras and G proteins:
    • Ras resembles only the alpha subunit of a G protein in structure.
    • They have different mechanisms of action and participate in different pathways.

Phosphorylation Cascade

  • A series of serine/threonine kinases phosphorylate and activate one another in sequence.
  • The cascade relays the signal from the plasma membrane to the nucleus.
  • Includes a three-kinase module called the MAP-kinase signaling module.
    • MAP kinase is phosphorylated and activated by MAP kinase kinase.
    • MAP kinase kinase is switched on by MAP kinase kinase kinase (activated by Ras).
  • MAP kinase phosphorylates various effector proteins.

Hyperactive Ras

  • A hyperactive Ras protein is dangerous to cells because it can cause cancer.
  • 30% of cancers have mutations in the RAS gene that make it hyperactive.

Modulation of Signaling Pathways

  • Signaling pathways can modulate one another (GPCRs and RTKs activate multiple intracellular signaling pathways).

Steroid and Thyroid Hormones

  • Signaling Mechanism:
    • Intracellular receptors (also known as nuclear receptors, which may be in the cytosol or nucleus).
  • Scheme of Action:
    1. Ligand (hydrophobic) enters the cell.
    2. Binds to a receptor, causing a conformational change.
    3. Binds to a gene at specific regulatory regions.
    4. Modulates gene activity (positively or negatively).
  • Chemical Description:
    • Hydrophobic
  • Receptor Identity:
    • Nuclear receptors
  • Receptor Location:
    • Cytosol or nucleus
  • Response Generation:
    • Hormones diffuse into the cell, bind to intracellular receptors, and the hormone-receptor complex acts as a transcription factor.
    • Modulates gene expression by binding to DNA response elements in the promoter regions of target genes.
    • Similar to the glucocorticoid receptor (GR).
  • Time Required for Response:
    • Typically takes hours to affect behavior.

Signal Transduction Turn-Off Mechanisms

  1. Ligand is metabolized.
  2. Receptor is degraded or sequestered.
  3. Second messenger is metabolized.
  4. Target proteins are dephosphorylated.