Lecture 16: Biosignaling

1. Lecture Overview

• Topics Covered:

  • Signal Transduction

  • G-Protein Coupled Receptors (GPCRs)

  • Enzyme-Linked Receptors and Integrins

  • Gated Ion Channels

  • Cell Cycle Regulation

2. Signal Transduction

• Definition: The process by which cells receive signals from external environments leading to physiological changes.

• Types of Signals: Include antigens, neurotransmitters, hormones, light, and touch.

• Receptors: Proteins that bind ligands, causing physiological effects.

  • Ligands can include ions, organic molecules, peptides, proteins, and sugars.

  • The relationship between ligand concentration and binding affinity is described by dissociation constant (Kd).

3. Membrane Signaling

• Types of Membrane Receptors:

  1. G protein-coupled receptors (GPCRs)

  2. Receptor tyrosine kinases (RTKs)

  3. Receptor guanylyl cyclase

  4. Gated ion channels

  5. Adhesion receptors (integrins)

• Mechanism:

  • Ligand binding leads to conformational changes, activating intracellular signaling cascades.

4. Transcription Regulation by Hormones

• Hormones Involved:

  • Steroid hormones, thyroid hormones, retinoids, and vitamin D can directly regulate gene transcription without needing external receptors.

  • These processes are slower yet result in long-lasting cellular responses.

5. G-Protein Coupled Signaling

• Structure and Function:

  • GPCRs: Integral membrane proteins consisting of seven transmembrane alpha helices; ~950 in humans.

  • Over 700 drugs target GPCRs, around 35% of all approved medications.

• Epinephrine: This hormone interacts with b-adrenergic GPCRs, causing various physiological effects like increased heart rate and energy mobilization (glycogen breakdown).

6. Signal Amplification

• Process:

  • Activation of few GPCRs can result in the activation of multiple adenylyl cyclase enzymes, leading to the production of numerous cAMP molecules, thereby amplifying the signal.

7. Self-Inactivation in G-Protein Signaling

• Signals like epinephrine are short-lived; down-regulation occurs through hydrolysis of GTP in G-protein subunits.

• Cholera and Pertussis Toxins: These keep adenylyl cyclase continuously activated, altering normal signal regulation.

8. Desensitization Mechanisms

• Desensitization involves b-arrestin binding to GPCRs, causing receptor endocytosis.

• Other desensitizing mechanisms include ligand hydrolysis and regulatory protein actions.

• Clinical Relevance: β-adrenergic receptors are targets for treatments involving heart conditions and asthma.

9. cAMP and PKA Functions

• Role: cAMP mediates multiple signaling pathways through its interaction with protein kinase A (PKA); specificity is determined by site-specific anchors.

• Subunit interactions (e.g., Ga, Gia) can inhibit or activate specific pathways influencing overall signaling.

10. Other Secondary Messengers

• Secondary messengers like inositol trisphosphate (IP3) and calcium signal through various pathways including calmodulin interaction.

11. Integrins

• Function: Integrins mediate cell adhesion and communicate extracellular signals, rearranging the cytoskeleton and activating internal signal cascades.

• They interact with Arg-Gly-Asp containing proteins, crucial for various biological responses.

12. Gated Ion Channels

• These channels regulate ion transport in response to membrane potential changes and ligand binding, playing critical roles in nervous system signaling.

13. Cell Cycle Regulation

• Intracellular regulation by cyclin-dependent protein kinases is vital for proper cell cycle progression:

  • CDK complexes are activated by growth factors and they phosphorylate target proteins to drive the cell cycle forward.

14. Apoptosis

• Definition: Programmed cell death responds to damaged macromolecules; it involves a cascaded response activating various caspases, leading to cell demise.