L11 Cell Signaling

Cell Signaling Lecture Notes

• Required Reading:

  • Morris text, Chapter 9
  • Section 9.1: Principles of Cell Signaling
  • Section 9.2: Distance Between Cells

• Objectives:

  • Signaling Receptors
  • G Protein-Coupled Receptors
  • Receptor Kinases

• Textbook References:

  • Morris text, Chapter 9 (pages 179-194)
  • Section 9.3: Signaling Receptors (pages 185-188)
  • Section 9.4: G Protein Coupled Receptors (pages 188-191)
  • Section 9.5: Receptor Kinases (pages 191-194)

Cell Communication

• All cells process environmental information.
• Communication is essential for coordinated activities.
• Chemical signals (hormones, neurotransmitters, CO2, H+) bind to specific receptors.
• Signals can originate from outside the organism or neighboring cells, and act over short or long distances.
• Examples of plant signals: ethylene
• Examples of animal signals: epinephrine

Receptor Activation and Types

• Receptor: A protein that receives and interprets information carried by a signaling molecule (ligand).
• Ligand binds to a ligand-binding site on a receptor.
• Binding causes a conformational shape change in the receptor.
• Shape change activates the receptor.
• Receptors can be intracellular or cell-surface receptors.

Intracellular Receptors

• Located inside the cell (cytoplasm or nucleus).
• Bind nonpolar signaling molecules (e.g., steroids).
• Steroids are hydrophobic and pass through the plasma membrane.
• Active steroid-receptor complexes act as transcriptional regulators, controlling gene expression.

Cell Surface Receptors

• Located on the cell surface.
• Bind polar signaling molecules (e.g., small proteins).
• Polar molecules cannot cross the plasma membrane.
• General structure:
  • Ligand-binding site (extracellular)
  • Extracellular domain
  • Transmembrane domain
  • Cytoplasmic domain
• Types:
  • G protein-coupled receptors
  • Receptor kinases
  • Ion channels

Cell Surface Receptors (2)

• Thousands of different receptor proteins on each cell surface.
• Receptors are grouped by activation mechanisms.

Cell Surface Receptors (3)

• Many receptors exist in "on" or "off" states.
  • "On" state: signaling molecule bound to receptor
  • "Off" state: signaling molecule not bound to receptor
• Examples: G protein-coupled receptors, receptor kinases, ligand-gated ion channels.

Signal Transduction, Response, and Termination

• Signal transduction (and sometimes amplification) occurs after a signaling molecule binds to a receptor.
  • Steps usually are similar for different ligands.

G Protein-Coupled Receptors

• Structure:
  • Ligand binding site (extracellular)
  • 7 transmembrane α-helices
  • G-protein binding site (cytoplasmic)
• Molecules used:
  • Small molecules
  • Many hormones
  • Neurotransmitters Signaling responsible for senses (sight, smell, taste).
• Activation:
  • ligand binds to receptor, activating receptor
  • Receptor activates a G protein (in the cytoplasm)
  • G proteins bind either GDP or GTP (guanine nucleotides). -G-protein + GTP = active
    • G-protein + GDP = inactive
• Signal Transduction:
  • Ligand binds to receptor then to G protein
  • GDP replaced with GTP, activating G protein.
  • Activated G protein activates other proteins in the signaling pathway.

G Protein-Coupled Receptors (3)

• Some G proteins have three subunits: α, β, γ (alpha, beta, gamma).

• The α subunit binds either GDP or GTP.

• α subunit + GDP = a three-subunit complex (inactive).

• Receptor activation replaces GDP with GTP, releasing the α from the subunit complex (activating the a subunit)

• Activated α subunit interacts with target protein = activates subsequent response

Example of G Protein Activation and Amplification: Adrenaline in Heart Muscle

• Adenylyl cyclase converts ATP to cAMP (a second messenger)
• cAMP activates protein kinase A.
• Activated protein kinase A phosphorylates heart proteins, increasing heart rate.
• Signal amplification occurs at multiple steps.

Amplification of Adrenaline Signalling

• A relatively small signal from adrenaline can result in a large response.
• Amplification occurs at multiple steps/targets within the signal cascade.
• Multiple protein targets are phosphorylated.

Termination of G Protein Signal

• Signal strength depends on how tightly the receptor holds onto the ligand.
• Ligand binding is not permanent.
• Signal turns off once the ligand is unbound.
• Deactivation of the G protein occurs (replaces GTP with GDP).
• Enzymes degrade cAMP to AMP

Termination of G Protein Signal (2)

• Phosphatases remove phosphate groups from proteins (dephosphorylation), inactivating them.

Receptor Kinases

• Kinase: an enzyme that adds a phosphate group to another molecule (phosphorylation).
• Phosphorylation typically activates a protein.
• Phosphate group comes from ATP.
• Shape change provided by phosphorylation gives new binding sites.
• Dephosphorylation removes the phosphate group (inactivates a protein).
• Phosphatases carry out dephosphorylation.

Receptor Kinase Activation

• Extracellular portion of the receptor binds a signaling molecule.
• Dimerization activates cytoplasmic kinase domains within the cytoplasmic tails of the receptor.
• Phosphorylation of the receptor activates specific sites.
• Phosphorylated sites provide docking sites for other proteins and activate them.

Receptor Kinases: Examples

• Involved in limb development, wound healing, and long-term responses (including changes in gene expression).
• The Kit receptor kinase is responsible for pigmentation in skin, feathers, scales, and hair.Mutations cause white patches.
• The MAP kinase pathway is an example (including Ras).

Ligand-Gated Ion Channels

• These receptors alter the flow of ions across the plasma membrane.
• Conformational shape change opens the channel.
• Channel remains open as long as the signaling molecule is bound.

Integration of Signaling Pathways

• Signaling pathways are not independent.
• Cells can receive and respond to multiple signaling molecules at the same time, which influences cellular response.
• Some pathways can enhance, cancel, or influence each other through "molecular cross-talk".

Test your knowledge of cell surface receptors and their critical roles in cellular communication. This quiz covers various types of cell-surface receptors, their functions, and the implications of signaling pathways. Dive into the fascinating world of cellular signaling and molecular interactions!