Cell Communication - Lecture 17

Lecture 17: Cell Communication - Enzyme-Linked Receptors

• Learning Objectives:
  • Understand the differences between fast and slow acting signaling pathways.
  • Explain different cellular signaling mechanisms (direct, paracrine, endocrine).
  • Distinguish membrane receptors from intracellular receptors based on ligands and modes of action.
  • Understand the similarities and differences among three classes of membrane receptors.
  • Identify downstream signal transduction mechanisms for GPCRs and RTKs.

Functions of Signaling Pathways

• Transduce: Convert the signal into a form that can execute a cellular response.
• Relay: Carry the signal from reception site to the site of action within the cell.
• Amplify: Increase the strength of the received signal.
• Integrate: Combine multiple signals to elicit a particular response.
• Distribute: Coordinate multiple responses in parallel.

Extracellular Signals Act Slowly or Rapidly

• Rapid (on/off response): Occurs within seconds to minutes, involving intracellular signaling pathways resulting in altered protein function or cytoplasmic machinery.
• Slow (sustained/long-term response): Takes minutes to hours, involving transcription, translation, and altered cell behavior like gene expression.

Example of Slow Signaling: Steroid Hormones

• Steroid hormones: Structurally similar to cholesterol, hydrophobic.
• Signal through intracellular receptors.
• Hormone binds to receptor in the cytosol.
• Receptor-hormone complex enters the nucleus.
• The complex binds to specific DNA regions, and activates gene transcription.

Cell Surface Receptors

• Three classes: Ion-channel coupled, G-protein coupled, and enzyme-linked receptors.

G-protein-coupled Receptors (GPCRs)

• Structure: Transmembrane protein with a signaling molecule binding extracellularly, and G proteins interacting intracellularly.
• Activation mechanism: Extracellular signal activates the G protein, causing dissociation of a subunit, which then triggers a cellular response.
• Deactivation mechanism: The G protein subunit hydrolyzes GTP to GDP, returning it to its inactive state.

G Proteins Dissociate into Two Signaling Complexes

• Subunits: Heterotrimeric G proteins have three subunits (α, β, γ).
• Mechanism: Binding of GTP causes the α subunit to detach from the βγ complex, initiating downstream signal transduction.

Reverse Reaction: Gₐ subunit inactivates

• Hydrolysis: The Gₐ subunit hydrolyzes GTP to GDP to switch itself off.
• RGS proteins: Can also participate in GTP hydrolysis aiding in G protein inactivation.

Some G Proteins Regulate Ion Channels

• Mechanism: G protein subunits can regulate the opening/closing of ion channels, influencing cellular processes such as heart rate regulation.

Some G Proteins Regulate Membrane-bound Enzymes

• Second messengers: Enzymes (e.g., adenylyl cyclase, phospholipase C) are activated by G proteins to produce second messengers inside the cell. Second messengers then initiate downstream signaling events.

Adenylyl Cyclase and Phospholipase C

• Adenylyl cyclase: Converts ATP to cyclic AMP (cAMP).
• Phospholipase C: Cleaves a lipid, producing inositol trisphosphate (IP₃) and diacylglycerol (DAG).

Cyclic AMP (cAMP) as a Second Messenger

• Mechanism: cAMP activates protein kinase A (PKA) initiating downstream signaling pathway, often influencing gene expression

Physiological functions of PKA and PKC

• PKA: Influences diverse aspects, including smooth muscle contraction, glycogen breakdown, nervous system processes (memory, neuronal excitation etc), and adipose tissue metabolism.
• PKC: Regulates various physiological functions, including: smooth muscle contraction, nervous system functions (memory, neuronal development), kidney functions, cell cycle progression.

Calcium Transients

• Role in cellular processes: Trigger a wide array of cellular events, surpassing simply affecting PKC. These include skeletal muscle contraction, regulated secretion (e.g., in neurotransmission), and fertilization-induced embryogenesis.

Fertilization

• Calcium wave: Induces embryogenesis in starfish.
• Fluorescent dyes: Load starfish eggs with a fluorescent calcium sensor to track calcium wave.

Receptor Tyrosine Kinases (RTKs)

• Ligands: Soluble or membrane-bound peptide/protein hormones (e.g., insulin, growth factors).
• Constitutively active mutants: Can send proliferative signals in the absence of normal stimuli, implicated in human cancers.

Receptor Tyrosine Kinases (RTKs) - Dimerization and Phosphorylation

• Mechanism: RTKs dimerize and phosphorylate each other's tyrosine residues on activation, triggering downstream signaling.
• Downstream signaling: Phosphorylated tyrosines serve as docking sites for other proteins, initiating cascades of reactions that influence cellular events.
• Termination: Tyrosine phosphatases terminate the signaling cascade.

Tyrosine Receptor Signaling Complexes

• Downstream signaling molecules: Various proteins, including phospholipases, lipid kinases, and kinases like Ras, execute downstream signaling.
• Pathway termination: Protein tyrosine phosphatases are involved in signaling termination.

Most receptor tyrosine kinases activate Ras protein

• Ras protein activation: Activated RTK initiates a series of events that activate the monomeric GTPase Ras via a Ras-GEF protein.
• Downstream signalling: Activated Ras initiates MAP Kinase (MAPK) pathways creating changes in protein activity and gene expression.

Ras Role in Mitogen-Activated Protein Kinase (MAP kinase) Cascade

• Cascade activation: Ras activates a kinase cascade involving multiple kinases (MAP kinase kinase kinase, MAP kinase kinase, and MAP kinase) culminating in changes in protein activity and gene expression.
• Mutations and cancer: Ras mutations frequently contribute to cancers by excessively activating signal transduction, driving uncontrolled cell proliferation.

RTKs Activate the PI 3-kinase-Akt Pathway

• Mechanism: Activated RTKs activate the PI3-kinase pathway, resulting in the phosphorylation of inositol phospholipids creating docking sites.
• Akt Activation: Leading to Akt activation which then influences cellular processes like cell growth, survival, and apoptosis inhibition.

Activated Akt Pathway

• Cell survival/growth promotion: Activated Akt inhibits apoptosis and promotes cell growth. Promoting an environment for cellular growth and proliferation.
• Inhibition of apoptosis: Enhances cell survival by halting apoptosis, influencing cellular growth behavior by stopping cell death.
• Inactive Bcl2 activation: Akt phosphorylates Bad (a protein that inhibits Bcl2, a pro-apoptotic protein) stimulating Bcl2 activity and reducing apoptosis likelihood.

Receptor Signaling is inactivated by Multiple mechanisms

• Mechanisms: Receptor sequestration, receptor downregulation, receptor inactivation, inactivation of signaling proteins, or production of inhibitory proteins.

Dive into the fascinating world of cell communication with our quiz on enzyme-linked receptors. This quiz will help reinforce your understanding of signaling pathways, receptor types, and the mechanisms of action involved in cellular signaling. Perfect for students looking to solidify their knowledge on this vital biological process!