Introduction to Signal Transduction

Signal Transduction

• Hormones facilitate homeostatic adaptations in an organism by altering protein activity and amount.
• Hormone-receptor interaction generates an amplified intracellular signal, which is converted into a chemical response.

Transmembrane Signaling

• Signal transduction involves the generation of second messenger signaling molecules, including:
  • Cyclic nucleotides (cAMP, cGMP)
  • Calcium
  • Phosphoinositide
  • Diacylglycerol (DAG)
• Many steps involve phosphorylation of receptors and downstream proteins.

Hormone Classification

• Hormones can be classified based on their solubility and receptor location.
• Hormones can also be classified based on the nature of the signal used, including:
  • Nuclear signals
  • Cytoplasmic signals

The General Process of Signal Transduction

• Signal transduction involves four basic steps:
  • A signal (ligand) interacts with a receptor.
  • The activated receptor interacts with cellular machinery, producing a second signal or a change in cellular protein activity.
  • The metabolic activity of the target cell undergoes a change.
  • The transduction event ends.

G-Protein-Coupled Receptors

• G protein-coupled receptors (GPCRs) indirectly activate enzymes that generate intracellular second messengers.
• Examples: β-adrenergic receptor system, which responds to epinephrine.
• GPCRs activate G proteins, which cycle between inactive GDP-bound and active GTP-bound forms.
• The activated G protein can activate different signaling cascades and effector proteins.

G-Protein-Coupled Receptors (continued)

• The Gα subunit binds to an effector and alters its activity.
• Effectors can include:
  • Adenylyl cyclase
  • Calcium channels
  • Phospholipase Cβ
  • cGMP phosphodiesterase
• The effector enzyme causes a change in the cytosolic concentration of a second messenger, which activates or inhibits downstream targets.

G-Protein-Coupled Receptors (continued)

• The Gα subunit eventually hydrolyzes the attached GTP to GDP, terminating the signal and deactivating the pathway.
• The Gα subunit re-associates with the Gβγ dimer, beginning a new cycle.

β-Adrenergic Pathway

• The binding of epinephrine to its receptor activates adenylyl cyclase.
• The activated adenylyl cyclase synthesizes cAMP, which acts as a second messenger.
• cAMP activates protein kinase A (PKA), which catalyzes the phosphorylation of target proteins.

cAMP-Dependent Protein Kinase A (PKA) Regulation

• cAMP binds to inactive PKA, activating it.
• The active PKA catalyzes the phosphorylation of target proteins on serine and threonine residues.
• The effects of cAMP are mediated by protein phosphorylation-dephosphorylation.

Hormones Act Through Calcium or Phosphatidylinositols (PIP2)

• The hydrolysis of phosphatidylinositol 4,5-bisphosphate leads to the activation of PKC and an increase in cytoplasmic Ca2+.
• Elevated Ca2+ activates Ca2+-calmodulin-dependent kinases and other enzymes, leading to altered physiologic responses.

Receptor Enzymes with Tyrosine Kinase Activity

• These receptors have an intrinsic protein tyrosine kinase activity and an extracellular domain that binds the ligand.
• Examples: insulin, EGF, and IGF-1 receptors.
• The ligand-receptor interaction stimulates tyrosine phosphorylation, initiating a cascade involving protein kinases, phosphatases, and other regulatory proteins.

Receptor Enzymes with Tyrosine Kinase Activity (continued)

• When insulin binds to its receptor, the receptor autophosphorylates on tyrosine residues, initiating a complex series of events.
• The phosphorylated insulin receptor phosphorylates insulin receptor substrates (IRS) on tyrosine residues.