3: Signal transduction

Section 1: Foundations - 3: Signal Transduction

Signal transduction is the fundamental process by which cells detect, amplify, and respond to extracellular signals (hormones, neurotransmitters, growth factors, light, odorants). This communication is essential for coordinating virtually all physiological functions, maintaining homeostasis, regulating growth, and enabling responses to the environment. The process converts an external signal into a specific intracellular response.

The core sequence involves:

1. Signal Molecule (First Messenger): A ligand binds specifically to a receptor protein.
2. Receptor: Proteins located either on the cell surface or inside the cell that undergo a conformational change upon ligand binding.
   • Cell Surface Receptors: Bind water-soluble ligands that cannot cross the membrane.
     • G-Protein Coupled Receptors (GPCRs): Largest family. Ligand binding activates an associated intracellular G-protein ($\alpha$, $\beta$, $\gamma$ subunits). The GTP-bound $\alpha$ subunit (or $\beta\gamma$ dimer) then activates or inhibits an effector protein (e.g., adenylyl cyclase, phospholipase C). Examples: epinephrine, glucagon receptors.
     • Receptor Tyrosine Kinases (RTKs): Ligand binding causes receptor dimerization and autophosphorylation on tyrosine residues. Phosphorylated tyrosines serve as docking sites for intracellular signaling proteins (e.g., GRB2, activating the Ras/MAPK pathway). Examples: insulin, growth factor receptors.
     • Ligand-Gated Ion Channels: Ligand binding directly opens/closes an integral ion channel, rapidly changing membrane potential or ion flux (e.g., acetylcholine at nicotinic receptors).
   • Intracellular Receptors: Bind lipid-soluble ligands (e.g., steroid hormones, thyroid hormone, vitamin D) that diffuse across the membrane. The ligand-receptor complex acts as a transcription factor in the nucleus, directly regulating gene expression.
3. Intracellular Signaling (Second Messengers & Pathways): The activated receptor initiates cascades inside the cell, often involving small, diffusible molecules called second messengers (e.g., cyclic AMP [cAMP], cyclic GMP [cGMP], inositol trisphosphate [IP3], diacylglycerol [DAG], calcium ions [Ca$^{2+}$]). These messengers activate specific protein kinases (e.g., Protein Kinase A [PKA] by cAMP, Protein Kinase C [PKC] by DAG/Ca$^{2+}$) which phosphorylate target proteins, altering their activity.
4. Effectors & Cellular Response: The final activated kinases or other signaling molecules modify effector proteins (enzymes, ion channels, cytoskeletal elements, transcription factors) to produce the physiological response (e.g., muscle contraction, glycogen breakdown, secretion, gene transcription).

Key Features:

• Signal Amplification: A single ligand-receptor interaction can activate many G-proteins or enzymes, each producing many second messengers, each activating many kinases, etc., hugely amplifying the initial signal (e.g., one epinephrine molecule can trigger glycogen breakdown yielding millions of glucose molecules).
• Specificity: Achieved by specific ligand-receptor binding and distinct intracellular pathways.
• Regulation & Termination: Responses are tightly controlled. Mechanisms include GTP hydrolysis by G$\alpha$, phosphodiesterase breakdown of cAMP/cGMP, phosphatase dephosphorylation of proteins, receptor internalization, and ligand degradation.