14-Transduction

Intracellular Signaling

  • Intracellular receptors

  • G protein-coupled receptors

  • Receptor tyrosine kinases

  • Elucidation of signal transduction pathways

  • Cytokine receptorsReferences: p. 586-587, 563-574, 577-581, 584-585

Intracellular Receptors

  • Many intracellular receptors are transcription regulators.

  • Recognized by small, lipid soluble signal molecules (e.g., steroids, amino acid-derived hormones).

  • Hormone binding leads to the expression of hormone-activated genes.

Cortisol Receptor

  • Cortisol: steroid hormone derived from cholesterol, produced by adrenal cortex.

  • Targets many organs, involved in long-term stress adaptation (e.g., raises blood glucose levels, mobilizes fat).

Mechanism of Action of Cortisol

  • The cortisol receptor functions as a transcription factor.

  • Inactive in cytosol, becomes active upon cortisol binding.

  • Binding causes conformational change, enabling transcription regulation.

  • Active receptor migrates to the nucleus, binds to enhancer sequences of target genes.

Activation Process

  1. Cortisol enters the cell.

  2. Binds to receptor, activating it.

  3. Complex translocates to the nucleus and binds to DNA to initiate transcription.

Signal Transduction

  • Definition: Relay of an intracellular signaling pathway to final targets through various intermediates.

  • Triggered by signal binding to surface receptors, leading to an intracellular cascade.

Signal Transduction Pathway Components

  • Extracellular signal molecules relay to receptors.

  • Primary transduction occurs in cytosol.

  • Second messengers amplify the signal within the cell.

  • Final targets execute the cellular response.

G Protein-Coupled Receptors (GPCRs)

  • Structure:

    • Extracellular receptor domain

    • Seven transmembrane domains

    • Cytoplasmic domain interacting with G proteins.

G Protein Structure and Activation

  • Activated by GTP; consists of three subunits (alpha, beta, gamma).

  • Inactive state: subunits are bound together with GDP.

  • Activation:

    • Receptor activation promotes GDP to GTP exchange on alpha subunit.

    • Results in dissociation of alpha from beta-gamma complex.

Functional Role of Activated G Protein

  • Both active alpha subunit and beta-gamma complex can interact with various targets within the cell.

Ion Channels and GPCRs

  • In heart muscle cells, the beta-gamma complex opens K+ channels in response to acetylcholine, decreasing heart rate.

Epinephrine Signaling

  • Produced by the adrenal medulla; involved in stress response.

  • Binds to a specific GPCR leading to activation of adenylyl cyclase, an enzyme that catalyzes the formation of cAMP from ATP.

Adenylyl Cyclase Activation

  • Activated by G protein alpha subunit.

  • cAMP functions as a secondary messenger, activating Protein Kinase A (PKA).

Protein Kinase A (PKA) Regulation

  • Inactive PKA: tetramer (2 regulatory and 2 catalytic subunits).

  • cAMP binding causes release of catalytic subunits, activating them.

  • PKA phosphorylates various target proteins, driving metabolic pathways—e.g., glycogen metabolism.

Glycogen Breakdown

  1. PKA activates phosphorylase kinase.

  2. Phosphorylase kinase activates glycogen phosphorylase.

  3. Glycogen phosphorylase converts glycogen to glucose-1-P, which can enter glycolysis after isomerization.

Calmodulin Activation Pathway

  • Triggered by G protein activation leading to phospholipase C activation.

  • Hydrolyzes PIP2 into DAG and IP3.

  • IP3 triggers Ca2+ release from the ER, activating calmodulin.

Functions of Calmodulin

  • Modulates a variety of processes by activating calmodulin-dependent kinases and phosphatases.

Wnt Signaling Pathway

  • Involved in cell differentiation; utilizes a family of secreted proteins.

  • Activation pathway affects transcription factors and gene expression governing cell fate.

Receptor Tyrosine Kinases (RTKs)

  • Function by dimerization upon signal binding.

  • Autophosphorylation of receptors activates downstream signaling cascades.

Ras-MAP Pathway

  • Controls cell proliferation and differentiation in response to growth factors.

  • Ras activation leads to a kinase cascade affecting gene expression.

Cytokine Receptors and JAK-STAT Pathway

  • Cytokines activate transcription factors through associated non-receptor tyrosine kinases (JAKs).

  • Binding leads to receptor dimerization and activation of STATs for gene expression.

Interferon-g Response Pathway

  • Cytokine released by NK cells; activates the JAK-STAT pathway leading to expression of IDO gene, resulting in apoptosis of target cells via tryptophan starvation.