CSF: Chapter 15B

Feedback Regulation Types

  • Positive Feedback

    • Involves a stimulus activating a protein (e.g., Protein B).
    • Protein B activates an activator that keeps another protein (e.g., Protein A) active.
    • Even without the stimulus, Protein B can continue activating Protein A.
    • Example:
    • Signal Kinase S → Phosphorylates E Kinase.
    • E Kinase phosphorylates itself, creating a feedback loop.
    • I (Phosphatase) works at a low basal rate, having a passive role in feedback.

  • Negative Feedback

    • Involves a stimulus activating Protein A, which then activates an inhibitor (e.g., Protein B).
    • This inhibitor shuts off Protein A, preventing response to the stimulus.
    • Example:
    • If Protein E activates an inhibitor that dephosphorylates E, the signaling response is regulated based on the timing of the inhibitor's activation.

Feedback Response Dynamics

  • Response without feedback:

    • E is active with presence of signal kinase.
    • Upon removal of signal kinase, E activation ceases.

  • Response with positive feedback:

    • Initial activation of E leads to prolonged activation due to self-activation.
    • E remains active even after the signal is removed, though slowly decreasing as I (phosphatase) kicks in.

  • Response with negative feedback:

    • Upon activation of E by signal kinase, negative feedback quickly diminishes E's activation as the inhibitor activates.
    • Timing of the feedback can result in different signaling responses (e.g., subdued response vs. oscillatory responses).

Importance of Individual Cell Responses

  • Grouping cells in population averages may mask individual variability.
  • Example with progesterone effect on MAP kinase in individual cells.
    • Initial graded response may appear as sigmoidal when pooled, but individual cells showed all-or-none behavior due to positive feedback maintaining activity.

Adaptation & Desensitization

  • Process where cells become less responsive over time, similar to human reactions.
    • Can occur via:
    • Negative feedback mechanisms.
    • Receptor modifications (phosphorylation, endocytosis).
    • Inhibition of signals by other proteins (delayed feedback).

G Protein-Coupled Receptors (GPCRs)

  • Characterized by 7-pass transmembrane proteins.
  • Activated by binding of signaling molecules leading to a conformational change.
  • Heterotrimeric G Proteins: Composed of alpha, beta, and gamma subunits.
    • Activation: Binding of GTP activates Gα subunit, which separates from Gβγ to initiate signaling.

Signaling through Cyclic AMP

  • Adenylyl cyclase converts ATP to cyclic AMP, a second messenger.

  • Protein Kinase A (PKA) is activated by cyclic AMP and phosphorylates target proteins, regulating numerous cellular functions.

  • Feedback inhibition: Cyclic AMP can also be hydrolyzed back to AMP, terminating the signal.

Responses to Specific Pathways

  • Diverse responses mediated by cyclic AMP in different tissues, e.g., heart rate increase, liver glycogen breakdown.
  • Example of cholera toxin interference with normal G protein signaling, leading to excessive diarrhea due to unregulated chloride transport.

Nitric Oxide (NO) Signaling

  • NO synthesized in response to GPCR activation, diffuses to smooth muscle causing relaxation.
  • Example: Nitric oxide synthase converts arginine to NO, which activates guanylyl cyclase to produce cyclic GMP, leading to muscle relaxation.

Termination of GPCR Signal

  • G Protein-coupled Receptor Kinases (GRKs) phosphorylate GPCR, allowing arrestin to bind, halting signaling.
  • Arrestin also mediates internalization of GPCRs, leading to their degradation or recycling.

Conclusion

  • Understanding these complex feedback mechanisms and receptor types is crucial for comprehending cellular signaling processes and their physiological impacts.