Lecture 5: Signalling across membranes

Overview of Protein Signaling Changes in Cells

• Discussion revolves around the mechanisms of how proteins change conformation within cells and the implications for cellular signaling.

Barriers to Cell Signaling

• First Barrier: Membrane

  • The membrane acts as a barrier that cells must navigate to send signals effectively.

  • Challenges:

  • Utilizing the membrane environment, e.g., recognizing pathogenic threats.

  • Reception of guidance cues that direct cellular movement.

  • Sensing signals related to cell death.

Types of Cellular Responses

• Fast Effects

  • Timeframe: Occur within seconds to minutes.

  • Mechanism: Involves altering the function of existing proteins already present in the cell.

  • Changes are generally reversible and primarily affect the cytoplasm, leading to effects such as cellular movement.

• Slow Effects

  • Timeframe: Take minutes to hours to manifest.

  • Mechanism: Typically require transcription and synthesis of new proteins.

  • These effects relate to processes that do not necessitate rapid responses.

Signaling Pathways

• Sigmoid Pathway: Each step corresponds to one activation interval.

  • The concept of inhibiting an inhibitory signal to activate a transcriptional regulator is fundamental in signaling pathways.

Movement and Binding Mechanisms

• Brownian Motion: Proteins within the cytoplasm use random motion to navigate and bind to the nucleus.

• Nuclear Receptor Binding:

  • Process:

  1. Ligand diffuses across the membrane and binds to a nuclear receptor.

  2. This binding activates direct gene transcription through ligand binding.

• Ligand Definition:

  • A ligand is defined as the molecule that binds to a receptor.

Cell Surface Receptors

• Requirement: Most signaling requires cell surface receptor proteins with the following characteristics:

  • External Region: Recognizes the ligand;

  • Example - NOTCH Signaling:

  • Process involves:

    1. Ligand binding triggers a shape change.

    2. Processing occurs inside the cell, releasing the intracellular domain.

    3. The intracellular domain interacts with the cellular machinery leading to subsequent signaling.

Channels and Responsiveness

• Ion Channels:

  • Voltage-Gated Channels: Respond to electrical changes in the membrane potential.

  • Mechanosensory Channels: (e.g., TRP channels)

  • Open in response to mechanical forces or pressure (stretch).

  • Mechanism includes:

    • Pressure-induced opening leading to ion influx.

G-Protein Activation

• Activation Process:

  • Release of GDP from G protein, allowing GTP to occupy the active site, leading to conformational changes.

  • The active G protein's alpha subunit separates from the beta and gamma subunits to propagate the signal.

• Significance of GTP Hydrolysis:

  • G proteins can hydrolyze GTP back to GDP, terminating signaling and recycling components for further signaling use.

Types of Cell Surface Receptors

• Receptor Types:

  • TPCRs (Transmembrane Protein Cell Receptors) are the most common cell surface receptors.

  • Generally activate secondary signaling pathways.

• TGF-β Receptors:

  • Composed of four subunits (two Type I and two Type II).

  • Binding of ligands leads to receptor activation and downstream signaling via kinase domains.

  • Autophosphorylation creates new binding sites for further signaling proteins.

Additional Notes on Receptor Dynamics

• Dimerization in Receptors:

  • Dimerization can change receptor conformation and function, impacting downstream signaling events.

• Insulin Receptor:

  • Another example highlighting the diversity of receptor types and their mechanisms of action.

• Co-receptors:

  • Molecules that bind alongside primary receptors to enhance the signaling process; relevance differs across signaling pathways.

Future Directions in Study

• Upcoming discussions will cover intracellular signaling mechanisms beyond the plasma membrane and how signals propagate within the cell to effect changes.