Signal Transduction and Cell Locomotion

Signal Transduction Overview

• Definition: Signal transduction is the process by which a cell converts an external signal into a specific internal response.
• Steps Involved:
  • Reception: A ligand binds to a receptor on the cell surface.
  • Transduction: The signal is relayed and amplified inside the cell.
  • Response: The cell executes a specific action based on the received signal.

Signal Molecule Interaction

• Non-Entering Ligand: A signal molecule (ligand) binds to a membrane receptor, causing a conformational change in the receptor, which activates intracellular signaling pathways. The ligand does not enter the cell.

Ligand Types

• Extracellular Ligand:
  • Remains outside the cell and binds to integral membrane proteins (e.g., peptide hormones).
• Cytoplasmic Ligand:
  • Composed of small or nonpolar molecules that diffuse across the cell membrane and bind inside the cell (e.g., steroid hormones like testosterone).

Receptor-Ligand Interactions

• Characteristics:
  • Highly specific interactions, resembling enzyme-substrate interactions.
  • Shape compatibility: Often described as a "lock-and-key" fit.
  • Binding: Primarily non-covalent interactions including hydrogen and ionic bonds.
  • Ligand binding triggers conformational changes in the receptor, similar to enzymatic reactions.

Levels of Signaling

• Local Signaling:
  • Paracrine: Affects nearby cells.
  • Autocrine: Affects the same cell that secreted it.
• Long Distance Signaling:
  • Endocrine: Hormonal signals travel via the bloodstream to distant target cells.

Paracrine vs. Endocrine Hormones

• Paracrine Hormone: Short-distance signaling acts on nearby cells.
• Endocrine Hormone: Travels through the bloodstream and acts on distant cells.

Signal Amplification

• Definition: Enables a small number of ligands to activate a large number of intracellular molecules.
• Significance:
  • Produces a strong internal response from a tiny external signal.
  • Enhances the speed and magnitude of cellular responses.

G-Protein-Coupled Receptors (GPCRs)

• Structure:
  • Consists of 7 transmembrane alpha-helices.
  • Contains a ligand-binding domain (extracellular) and a G-protein interaction domain (intracellular).
• Function: Upon ligand binding, GPCRs activate G-proteins within the cell.

G-Proteins

• Structure:
  • Composed of three subunits: alpha (α), beta (β), and gamma (γ).
  • β and γ are tightly associated while α can detach when activated.
• Activation Cycle:
  • GDP-bound α is inactive; GTP-bound α is active.

Mechanisms of G-Protein Signal Transduction

1. Ligand binds to GPCR.
2. GPCR undergoes conformational change.
3. GPCR activates G-protein by exchanging GDP for GTP on the α subunit.
4. The activated α subunit dissociates from the βγ complex and interacts with target proteins (e.g., adenylyl cyclase).

cAMP: A Second Messenger

• Definition: Cyclic AMP (cAMP) is a second messenger involved in various signaling pathways.
• General Pathway:
  1. Active Gα activates adenylyl cyclase.
  2. Adenylyl cyclase converts ATP to cAMP.
  3. cAMP activates protein kinase A (PKA).
  4. PKA phosphorylates target proteins leading to a cellular response.

cAMP Regulation

• Adenylyl Cyclase: Produces cAMP when activated by Gα-GTP.
• cAMP Phosphodiesterase: Degrades cAMP to AMP, terminating the signal.

Key Enzyme Definitions

• Kinase: Adds a phosphate group to a molecule using ATP.
• Phosphorylase: Adds inorganic phosphate without using ATP.
• Phosphatase: Removes a phosphate group from a molecule.

Glycogen Metabolism Pathways

• Glycogenesis (Synthesis):
  • Converts glucose to glucagon for storage.
• Glycogenolysis (Breakdown):
  • Converts glycogen back to glucose for energy.

Regulation of Glycogen Phosphorylase

• Mechanism: Activated by phosphorylation via PKA.
• Forms:
  • Inactive: phosphorylase b (unphosphorylated)
  • Active: phosphorylase a (phosphorylated)

Fight or Flight Response via Epinephrine

1. Epinephrine binds GPCR on liver/muscle cells.
2. GPCR activates Gα protein.
3. Gα activates adenylyl cyclase.
4. Adenylyl cyclase increases cAMP production.
5. cAMP activates PKA leading to phosphorylation of key enzymes.

IP3/DAG Signaling Pathway

• Activation: Phospholipase C (PLC) activated by G-protein or RTK cleaves PIP2 forming IP3 and DAG.
• Effects:
  • IP3 releases Ca2+ from the ER.
  • DAG activates protein kinase C (PKC).

Calcium Signaling

• Basal levels of cytoplasmic [Ca2+]: ~10^-4 mM (low).
• [Ca2+] in ER/Extracellular: Higher than cytoplasm to control signaling.
• Calmodulin: A small protein with four binding sites for Ca2+. Changes conformation when Ca2+ binds, regulating other proteins.

Blood Vessel Structure

• Inner Layer: Endothelium (composed of endothelial cells).
• Middle Layer: Smooth muscle cells.
• Outer Layer: Connective tissue (collagen and elastin fibers).

Vasodilation vs Vasoconstriction

• Vasodilation: Relaxation of smooth muscle, resulting in vessel widening.
• Vasoconstriction: Contraction of smooth muscle, leading to vessel narrowing.

Steps Involved in Calcium-Mediated Vasodilation

1. Signal molecule binds to endothelial cells.
2. Production of IP3 leads to Ca2+ release from the ER.
3. Ca2+ binds to calmodulin.
4. Activated calmodulin stimulates nitric oxide synthase (NOS).
5. NOS produces NO.
6. NO diffuses to smooth muscle cells.
7. NO activates guanylyl cyclase converting GTP to cGMP.
8. cGMP leads to muscle relaxation and vasodilation.

Role of cGMP-Phosphodiesterase

• Breaks down cGMP to GMP, terminating vasodilation and resulting in muscle contraction.

Effects of Nitroglycerin and Viagra

• Nitroglycerin: Increases NO production, enhancing vasodilation.
• Viagra: Inhibits cGMP-phosphodiesterase, preventing cGMP breakdown and prolonging vasodilation.

Enzyme-Coupled Receptors: RTKs

• Definition: Receptors with intrinsic enzyme activity or associated with an enzyme post-ligand binding.
• Structure: Extracellular domain for binding, single transmembrane helix, and an intracellular tyrosine kinase domain.
• Function: Dimerization and autophosphorylation activate downstream pathways.

Growth Factors and Signaling Pathway

• Definition: Signaling molecules that stimulate cell growth and differentiation (e.g., EGF, PDGF).
• Pathway Steps:

1. Growth factor binds RTK.
2. RTKs dimerize and autophosphorylate.
3. Adaptor proteins bind phosphorylated tyrosines.
4. Activate downstream pathways (e.g., RAS-MAPK) leading to growth.

Insulin/Glucagon System and Blood Glucose Regulation

• High blood sugar: Insulin promotes uptake and glycogenesis.
• Low blood sugar: Glucagon promotes glycogenolysis and gluconeogenesis.

Diabetes Overview

• Definition: Chronic high blood glucose levels due to insulin deficiency or resistance.
• Types:
  • Type I: Autoimmune destruction of pancreatic β-cells.
  • Type II: Insulin resistance mainly tied to lifestyle.
  • Gestational diabetes: Temporary insulin resistance during pregnancy (Type II).

Cytoskeleton Functions

• Provides structure, organizes components, enables transport, powers movement, and is essential for division.

Cytoskeletal Elements

• Microtubules: Organize cell interior, transport vesicles, and form mitotic spindles. Diameter ~25 nm.
• Microfilaments: Maintain shape and drive movement. Diameter ~7 nm.
• Intermediate Filaments: Provide tensile strength and support. Diameter ~7-12 nm, varies by cell type.

Motor Proteins and Functions

• Kinesin: Moves toward the plus end; transports vesicles outward.
• Dynein: Moves toward the minus end; transports vesicles inward.

Cell Movement Types

1. Intracellular movement (organelle transport).
2. Whole-cell movement (crawling).
3. Movement across surfaces (cilia-driven).

Cilia vs Flagella

• Cilia: Short, numerous, and beat to move fluids.
• Flagella: Long, few, propel cells (e.g., sperm).

Ciliary Structure

• Both have 9+2 arrangement of microtubules.
• Dynein arms facilitate movement by creating bending through inter-microtubule interaction.

Cancer and Metastasis

• Cancer: Uncontrolled cell growth.
• Metastasis: Spread of cancer cells to other body parts.

Leukocyte Extravasation and Cancer Metastasis

• Mechanisms are similar: both leukocytes and cancer cells must migrate through endothelium, utilizing adhesion molecules and cytoskeletal changes.