Signalling Pathways and Lipid Mediators Notes

Cellular Communication

  • Purpose: Essential for cellular function and organism viability.
  • Mechanisms:
    • Signalling Molecules: Facilitate communication between cells.
    • Hormones: Systemic messengers (e.g., adrenaline).
    • Autacoids: Local signalling molecules (e.g., prostaglandins).
    • Neurotransmitters: Signal transmission across synapses.

Signal Reception & Transduction

  • Mechanism Sequence:
    1. Release of primary messenger.
    2. Reception of primary messenger on receptor.
    3. Activation of secondary messengers.
    4. Effector activation causes physiological response.
    5. Termination of the signal.
  • Amplification: Involves secondary messengers (intracellular) and primary messengers (extracellular).

Receptor Superfamilies

  • Types of Receptors:
    • Cell Surface:
    • Ligand-gated Ion Channels: Very fast (milliseconds).
    • G protein-coupled Receptors (GPCRs): Fast (seconds).
    • Kinase-linked Receptors: Intermediate speed (minutes).
    • Intracellular:
    • Nuclear Receptors: Very slow (hours-days).

Ligand-Gated Ion Channels

  • Structure: Typically consist of 5 subunits forming a channel.
  • Function: Upon activation by agonist, channels allow ions (e.g., Na+, K+, Ca2+, Cl-) to flow.
  • Examples:
    • P2X Receptor: ATP-gated, allows cation flow.
    • GABA Receptors: Chloride ion channel.
    • Nicotinic Acetylcholine Receptors: Sodium and potassium channel.

G Protein-Coupled Receptors (GPCRs)

  • Represent 3-4% of the human genome with ~800 functional GPCRs.
  • Major role in cell communication; target for 1/3 of drugs.
  • Types of Ligands:
    • Endogenous: Monoamines, amino acids, peptides, etc.
    • Sensory Stimuli: Light, taste, odorants.

Signal Transduction via GPCRs

  • Process Example: Adrenergic receptors.
  • Steps:
    1. Release of first messenger (e.g., adrenaline).
    2. Reception at b2AR (beta-adrenergic receptor).
    3. Activation of second messengers (e.g., cAMP).
    4. Activation of effectors such as Protein Kinase A (PKA).
    5. Termination of the signal (clearance of adrenaline, hydrolysis).

Receptor Tyrosine Kinases (RTKs)

  • Function: Mediate cell effects mainly through phosphorylation, including autophosphorylation.
  • Hormonal Responses: Insulin, epidermal growth factor, and growth hormone.

Nuclear Receptors

  • Type of receptors that bind lipophilic hormones (e.g., thyroid hormones, retinoic acid).
  • Regulates gene expression and acts as transcription factors.
  • Examples include PPARs, RARs, and ER.

Fatty Acids as Signalling Molecules

  • Fatty acids act as signalling metabolites.
  • Types of Signalling Molecules: Prostaglandins, leukotrienes, lipoxins, resolvins, etc.
  • Receptor Types:
    • Nuclear Receptors: e.g., PPARs.
    • Cell Surface Receptors: GPRs such as FFA1, FFA2, etc.

Eicosanoids as Signalling Molecules

  • Derived from 20-carbon fatty acids (e.g., arachidonic acid).
  • Act as autacoids providing local cell signals.
  • Enzymes in Fatty Acids Metabolism:
    • Lipoxygenases (LO) and cyclooxygenases (COX) produce various signalling molecules such as prostaglandins and thromboxanes.