Case 9

Synaptic Signaling

• Neurotransmitters bind to receptors on the receiving cell, triggering a chemical change.
• This change often involves opening ion channels and altering the electrical potential across the membrane.
• Neurotransmitters are quickly broken down or reabsorbed by the sending cell, resetting the synapse for the next signal.
• Primarily uses neurotransmitters like dopamine, serotonin, and acetylcholine.

Autocrine Signaling

• A cell signals to itself by releasing a ligand that binds to receptors on its own surface.
• Plays a role in cell development, helping cells maintain their identities.
• Important in cancer, possibly contributing to metastasis.
• Many signals have both autocrine and paracrine effects.
• Commonly uses signaling molecules like cytokines and growth factors.

Endocrine Signaling

• Cells use the circulatory system to transmit signals over long distances.
• Specialized cells produce hormones and release them into the bloodstream.
• Hormones travel to target cells in distant parts of the body.
• Endocrine glands, such as the thyroid, hypothalamus, pituitary, gonads, and pancreas, release hormones.
• Hormones are master regulators of development and physiology.
• Uses hormones like insulin, estrogen, and adrenaline.

Signaling Through Cell-Cell Contact

• Gap junctions (in animals) and plasmodesmata (in plants) connect neighboring cells.
• These channels permit small signaling molecules (intracellular mediators) to diffuse between cells.
• Allows for coordinated responses to signals received by only one cell in a group.
• Uses membrane-bound signals like ligands and their corresponding receptors on adjacent cells.

Molecules Used in Cell Signaling

• Hydrophobic:
  • Steroid hormones
  • Fatty acid derivatives
  • Gasses
• Hydrophilic:
  • Neurotransmitters
• Gasses:
  • NO (Nitric oxide)
  • CO (Carbon monoxide)
• Ions:
  • K+ (Potassium)
  • Na+ (Sodium)
  • Ca2+ (Calcium)
• Amino acids
• Peptides
• Proteins
• Nucleotides:
  • miRNA (microRNA)

Protein Secretion

• Exocytosis
• Shaving (releasing portions of a protein)

MicroRNA

• Single-stranded RNA
• Requires protection from degradation:
  • Connecting to a protein (HDL, RBP)
  • Packing into a vesicle

Direct Connections and Communication

• Gap junctions:
  • Channels between cells that allow transport of ions, water, and other substances.
  • Formed by connexins forming connexons.
  • Crucial in cardiac muscle, allowing synchronized contraction.
  • Allow passage of small molecules like Ca2+, cyclic AMP, nucleotides, and amino acids.
  • Highly responsive to changes, opening and closing within seconds.
• Tight junctions:
  • Create a watertight seal between cells.
  • Composed of claudins, forming strands that contribute to a tight seal.
  • Prevent leakage of fluids between cells.
• Anchoring junctions:
  • Provide mechanical stability by linking cytoskeletons of cells or cells to extracellular matrix.
  • Important for structural integrity, especially in tissues exposed to stress.
  • Adherens junctions: Link actin cytoskeletons of adjacent cells, maintaining tissue architecture and cell shape.

Nuclear Receptors

• Ligand binding exposes DNA-binding domains, allowing them to alter gene transcription.
• Found in the promoter region of genes, influencing gene expression.
• Ligands include:
  • Cholesterol-derived hormones (cortisol, estradiol, testosterone, vitamin D3)
  • Tyrosine-derived hormones (thyroxine)
  • Vitamin A derivative (retinoic acid)
• Orphan receptors are receptors with unknown ligands.

Signal Transduction:

• First messenger: Signal originating outside the cell.
• Second messenger: Signal inside the cell.
• Can be water-soluble or lipid-soluble.
• Signal amplification often occurs, such as autophosphorylation.

Cell-Surface Receptors:

• Extracellular domain: Binds to ligands on the cell surface.
• Hydrophobic domain: Spans the cell membrane.
• Intracellular domain: Transmits signals inside the cell.
• Ligand-gated ion channels:
  • Open in response to ligand binding.
  • Channel allows specific ions to pass through the membrane.
• Enzyme-linked receptors: (catalytic receptors)
  • Have an extracellular ligand-binding domain and an intracellular domain with enzymatic activity.
  • Ligand binding activates the enzyme, leading to intracellular signaling.

Enzyme-Linked Receptor Subclasses:

• 1. Receptor Tyrosine Kinases (RTKs):
  • Have intrinsic tyrosine kinase activity.
  • Upon ligand binding, dimerize and autophosphorylate on tyrosine residues, activating downstream signaling pathways.
  • Examples: EGFR, Insulin receptor, VEGFR
  • Ligands: Growth factors, insulin
• 2. Receptor Serine/Threonine Kinases:
  • Phosphorylate serine or threonine residues on target proteins.
  • Examples: TGF-β receptors
  • Ligands: TGF-β, BMPs
• 3. Tyrosine Kinase-Associated Receptors:
  • Associate with intracellular tyrosine kinases (like JAKs) for phosphorylation.
  • Examples: Cytokine receptors (interleukin receptors, erythropoietin receptors)
  • Ligands: Cytokines, growth hormones
• 4. Receptor Guanylyl Cyclases:
  • Possess guanylyl cyclase activity, generating cGMP from GTP.
  • Example: ANP receptor
  • Ligands: ANP, BNP
• 5. Receptor Tyrosine Phosphatases:
  • Have phosphatase activity, removing phosphate groups from tyrosine residues.
  • Typically regulate signaling pathways.
  • Example: CD45
  • Ligands: Involved in immune regulation.