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Lecture 6 and 7: Receptors and Signal Transduction

Phosphorylation/Dephosphorylation in Metabolism

  • Metabolic Pathways: Many metabolic pathways are controlled by the phosphorylation/dephosphorylation of key enzymes.
  • Enzyme Specificity: Whether a phosphorylation event activates or deactivates an enzyme is enzyme-specific.
  • Protein Functions: Many proteins involved in kinase signaling can be phosphorylated at various specific sites. Different combinations of phosphorylations (Pi) can alter protein functions by changing their interacting partners.
    • Example: Interactions of p53, p63, p73 with 53BP1 may be affected by their phosphorylation states.

Receptor/Signal Transduction Pathways

  • Function:
    • Specific Responses: Receptor pathways provide very specific responses by activating selective enzymes.
    • Signal Amplification: These pathways amplify signals from stimuli.
    • Multiple Changes: They can induce multiple intracellular changes simultaneously.
    • Pathway Intersections: Linear pathways intersect and impact other pathways in complex dynamics.

Major Signaling Pathways Influenced by Nutrition

  • Cyclic AMP (cAMP)
  • AMP-Activated Protein Kinase (AMPK)
  • Mitogen-Activated Protein Kinase (MAPK)
  • DNA Damage Response (ATM/ATR)
  • Cell Cycle Regulation
  • Wnt/β-Catenin Pathway
  • Nuclear Receptors

Nutrient Processing in the Liver

  • Glycogen Storage: Upon nutrient consumption, glycogen synthase aids the liver in storing excess carbohydrates as glycogen. Glycogen consists of glucose molecules linked by alpha-1,4 linkages.
  • Glycogen Release: During fasting, the liver releases glucose from glycogen stores to supply glucose to the brain and heart. This process involves the enzyme glycogen phosphorylase.

cAMP Signaling and Glycogen Phosphorylase Activity

  • Glycogenolysis Process: In the liver, glycogen is broken down into glucose via glycogenolysis, which is catalyzed by glycogen phosphorylase.
  • Regulation: Glycogen phosphorylase is regulated by both covalent and allosteric mechanisms.
    • Covalent Regulation: Mediated by hormones such as:
      • Glucagon
      • Catecholamines (epinephrine and norepinephrine)
    • Hormonal Action: These hormones bind to cell surface receptors, activating adenyl cyclase, which converts ATP to cAMP. Active cAMP phosphorylates glycogen phosphorylase and other proteins.

Overview of Covalent Regulation of Glycogen Phosphorylase

  • Enzyme Forms:
    • Phosphorylase b (Inactive)
      • Stimulated by glucagon and epinephrine (hormones) and activated by cAMP.
    • Phosphorylase a (Active)
      • Converts glycogen to glucose-1-phosphate (an active form).
  • Regulatory Factors: Positive regulation by cAMP; negative regulation by ATP and glucose-6-phosphate, affecting the enzyme's equilibrium between active and inactive states.

Glucagon Signaling Pathway (cAMP Pathway)

  • Overview of pathway components and flow:
    • Inactive and active states of glycogen synthase and phosphorylase.
    • Single activation events lead to cascades involving multiple protein kinases.
    • Enhancements and inactivations occur at various stages by different factors:
      • Phosphatases remove phosphates, affecting enzyme activation states.

Allosteric Regulation of Glycogen Phosphorylase

  • Activation and Inhibition:
    • Allosteric Activation: AMP accumulation indicates low energy, leading to activation of glycogen phosphorylase.
    • Allosteric Inhibition: ATP acts as an inhibitor; caffeine similarly inhibits the enzyme.

cAMP Signaling Effects & Role in Energy Homeostasis

  • Various cellular processes affected by changes in cAMP concentrations, encompassing:
    • Kinase activity modulation
    • Cellular metabolism adjustments
    • Lipid and glycogen metabolism
    • Protein synthesis regulation

AMP-Activated Protein Kinase (AMPK) Signaling

  • Function: AMPK acts as a cellular glucose sensor that detects energy levels by monitoring the AMP:ATP ratio.
  • Activation:
    • An increase in the AMP:ATP ratio indicates low energy (e.g., during hypoxia or strenuous exercise).
  • Pathway Regulation:
    • When active, AMPK promotes ATP-generating pathways while inhibiting ATP-consuming pathways such as lipid, glycogen, and protein synthesis.

GLUT4 and AMPK

  • GLUT4 Translocation: AMPK phosphorylates GLUT4, which translocates from the intracellular compartment to the cell membrane, enhancing glucose uptake.
  • Pharmacological Applications:
    • Activation of AMPK is a target for drugs like Metformin, aiding in type II diabetes treatment through insulin-independent mechanisms.