ch 10

Essential Biochemistry Notes

Chapter 10: Signaling

Section 10.1: General Features of Signaling Pathways

• Learning Objective

  • Summarize the properties of a receptor

  • Quantify ligand binding in terms of a dissociation constant

  • Recount the events in the two main types of signal transduction

  • Describe the factors that limit signaling

• Overview of Signaling

  • Receptor: Protein that binds to a signalling molecule (ligand) to initiate a cellular response.

  • Signal transduction: Process where a signaling molecule activates a receptor that leads to cellular responses.

• Binding Affinity (Ka)

  • Ligands bind to receptors with a characteristic affinity summarized by the equilibrium constant $K_d$.

  • $K_d$ (dissociation constant) represents the ligand concentration at which half of the receptor molecules are occupied by the ligand.

  • Equation:
    $K_d = rac{[R][L]}{[R \bullet L]}$

  • Where

    • $[R]$: Total receptor concentration

    • $[L]$: Ligand concentration

• Signal Transduction Mechanisms

  1. G-Protein Coupled Receptors (GPCRs):

  • Ligand binding causes conformational change in the receptor.

  • Activates G protein by exchanging GDP for GTP.

  • G protein activates intracellular proteins, leading to cellular effects through second messengers (e.g., nucleotides, lipids).

  • Example: Changes in metabolic activity and gene expression by modifying target proteins.

  1. Receptor Tyrosine Kinases (RTKs):

  • Kinases transfer a phosphoryl group from ATP to another molecule, particularly on tyrosine residues.

  • Ligand binding induces dimerization, autophosphorylation, and activation of downstream signaling cascades.

  • Example: Changes in metabolic activity and gene expression through a series of kinase activations.

• Multistep Pathways:

  • Multistep pathways amplify signals, allowing a small extracellular signal to yield a significant cellular response.

  • Regulation is essential; all processes must be appropriately turned on and off to maintain homeostasis.

Section 10.2: G Protein Signaling Pathways

• Learning Objective:

  • Describe signaling via G-protein-coupled receptors.

  • Summarize the roles of receptors, G proteins, nucleotides, and lipids in signaling.

  • Describe how a kinase is activated.

  • List the mechanisms that limit, compete, and terminate the G protein signaling pathway.

  • Explain differential cellular responses to the same hormone and vice versa.

  • Provide examples of GPCRs and their ligands.

• B2-Adrenergic Receptor Process:

  1. Epinephrine binds to B-adrenergic receptor.

  2. Ligand-receptor complex activates G protein, exchanging GDP for GTP on G protein.

  3. Activated G-protein subunit separates and activates adenylyl cyclase, enhancing formation of cyclic AMP (cAMP).

  4. cAMP activates protein kinase A (PKA), which phosphorylates target proteins leading to a biological response.

  5. cAMP is degraded by phosphodiesterase, reversing PKA activation and terminating the signal.

• Opioid GPCRs:

  • Approximately 1/3 of therapeutic drugs target GPCRs.

  • Opioids (e.g. morphine, fentanyl) bind to specific GPCRs, resulting in reduced pain signals.

  • Over time, receptor sensitivity decreases leading to reduced endorphin production.

• GPCRs and Sensory Perception:

  • Olfactory receptors and gustatory receptors use GPCRs to perceive smells and tastes, respectively.

  • Olfaction: Humans have numerous GPCRs for different odorants enabling the distinction of thousands of smells.

  • Gustation: Sweet, bitter, and umami tastes are sensed through GPCRs, while sourness and saltiness have alternative signaling methods.

Section 10.3: Receptor Tyrosine Kinases (RTKs)

• Learning Objective:

  • Describe the RTK signaling pathway.

  • Compare G protein–coupled receptors (GPCRs) with RTKs.

  • Distinguish activation mechanisms for target proteins in RTKs.

  • Understand the different time scales of response mediated by kinases and transcription factors.

• RTK Structure:

  • RTKs have:

  • An extracellular ligand-binding domain

  • A single transmembrane helix

  • An intracellular tyrosine kinase domain

  • They function as dimers, altering conformation upon ligand binding, promoting autophosphorylation which enhances kinase activity.

• Insulin Receptor as an Example:

  • Insulin binds to the RTK, causing a conformational change that facilitates autophosphorylation and activation of signaling cascades involved in cell growth and metabolism.

• Ras Pathway:

  • Ras is a critical component in many RTK signaling pathways, starting kinase cascades that amplify the signal, leading to changes in gene expression in the nucleus.

Section 10.4: Lipid Hormone Signaling

• Learning Objective:

  • Compare lipid signaling to other signal transduction pathways.

  • Identify lipid hormones and their mechanisms.

  • Explain the structure-function relationship of eicosanoids versus traditional signaling molecules.

• Lipid Hormones Overview:

  • Lipid hormones can pass through the plasma membrane due to their hydrophobic nature.

  • They bind to intracellular receptors and can regulate gene expression by forming complexes with DNA.

  • Examples include retinoic acid and steroids.

  • Lipid hormone signaling differs from GPCR signaling due to slower, sustained responses as opposed to immediate signaling effects.

• Lipid Hormone Action:

  • Involves direct binding to DNA, leading to transcription factor activation and modulation of gene expression.

Additional Notes

• Desensitization of Receptors:

  • High ligand concentrations can lead to receptor endocytosis, lowering cellular sensitivity to subsequent signals.

  • This mechanism is crucial in understanding addiction and tolerance in pharmacology.

• Importance of Cross-Talk:

  • Interaction of various signaling pathways is termed cross-talk; it plays a significant role in cellular response and signal integration.