Receptor Types

To explain the concept of drug action with respect to: receptor theory, enzyme interactions, and physicochemical interactions.

To explain receptor activity with regard to: ionic fluxes, second messengers and G proteins, nucleic acid synthesis, evidence for the presence of receptors, regulation of receptor number and activity, structural relationships.

Receptor Types

A receptor is a protein, usually in the cellular membrane, to which a ligand may bind to generate a response.

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• Intracellular receptors
  May be either cytoplasmic or intra-nuclear.
  • Intranuclear receptors are activated by lipid soluble molecules (such as steroids and thyroxine) to alter DNA and RNA expression
    This results in an alteration of production of cellular proteins, so the effects tend to be slow acting.

• Enzyme-linked receptors
  Are activated by a ligand and cause enzymatic activity on the intracellular side. They can be either:
  • Monomers
  • Dimers
    Where two proteins join, or diamerise, on binding of a ligand.

• Ion-channel receptors (ionotropic)
  Create a channel through the membrane that allows electrolytes to flow down their electrical and concentration gradients. They can be either:
  • Ligand-gated channels
    Undergo conformational change when a ligand is bound. There are three important families of ligand channels:
    • Pentameric family
      Consist of five membrane spanning subunits. Include:
      • Nicotinic ACh receptor
      • GABA_A receptor
      • 5-HT₃ receptor
    • Inotropic glutamate receptors Bind glutamate, a CNS excitatory neurotransmitter. Include:
      • NMDA receptor
        High Ca²⁺ permeability
    • Inotropic purinergic receptors
      Form cationic channels that are permeable to Ca²⁺, Na⁺, and K⁺
      Activated by ATP
      
      
  • Voltage-gated channels
    Open when the threshold voltage is reached, facilitating electrical conduction in excitable tissues.
    • In their normal physiological state, voltage gated channels do not generally behave as receptors for a ligand, however some drugs (e.g. local anaesthetics) will bind to voltage gated channels to exert their effect
    • Have a common 4-subunit structure (each with 6 transmembrane segments) surrounding a central pore
      This pore is selective for the particular ion, which include:
      • Na⁺
        • Located in myocytes and neurons
        • Important in generating and transmitting an action potential by permitting sodium influx into cells
        • Inhibited by local anaesthetics, anti-epileptics, and some anti-arrhythmics
      • Ca²⁺
        Divided into subtypes, including:
        • L
          Muscular contraction.
        • T
          Cardiac pacemaker.
        • N/P/Q
          Neurotransmitter release.
        • K⁺
          Located in myocytes and important in repolarisation following an action potential.
    • Undergo a conformational change when the threshold potential is reached
      This is sensed by the S4 helix, which acts to open and close the channel.
    • Exist in one of three functional states:
      • Resting
        Pore is closed.
      • Active
        Pore is open, and ions can pass.
      • Inactive
        Transient refractory period where the pore is open, but ions cannot pass. This creates the absolute refractory period of a cell.

• G-protein coupled (metabotropic) receptors:
  G-proteins are a group of heterotrimeric (containing three units; α, β, γ) proteins which bind GDP. When stimulated, the GDP is replaced by GTP and the α-GTP subunit dissociates to activate or inhibit an effector protein. The effect depends on the type of α-subunit:
  • G_s proteins
    Are stimulatorly. These
    • Increase cAMP, leading to a biochemical effect
  • G_i proteins
    Are inhibitory. These:
    • Inhibit adenylyl cyclase, reducing cAMP
  • G_q proteins
    Have a variable effect, depending on the cell. These:
    • Activate phospholipase C
      This affects the production of:
      • Inositol triphosphate (IP₃)
        Stimulates Ca²⁺ from the SR, affecting enzymatic function or causing membrane depolarisation.
      • Diacylglycerol (DAG)
        Activates protein kinase C, which has cell-specific effects.
• Activate intracellular second messenger proteins when stimulated
  Second messenger systems:
  • Result in both transmission and amplification of a stimulus, as a single activated receptor can activate multiple proteins and each activated protein may activate several other intermediate proteins
    • This is known as a G-protein cascade

Enzyme interaction

Drugs can interact with enzymes by antagonism or by being a false substrate.

Enzyme antagonism

Most drugs which interact with enzymes inhibit their activity. This results in:

• Increased concentration of enzymatic substrate
• Decreased concentration of the product of the reaction

Drugs can be competitive, non-competitive, or irreversible inhibitors of enzymatic activity. Examples include:

• Ramipril is a competitive inhibitor of angiotensin-converting enzyme.
• Aspirin is an irreversible inhibitor of cyclo-oxygenase.

False substrates

False substrates compete with the enzymatic binding site, and produce a product. Examples include:

• Methyldopa is a false substrate of the enzyme dopamine decarboxylase.

Physicochemical

Drugs whose mechanism of action is due to their physicochemical properties. Examples include:

• Mannitol reduces ICP because it increases tonicity of the extracellular compartment (and is unable to cross the BBB), drawing free water from the intracellular compartment as a consequence.
• Aluminium hydroxide reacts with stomach acid to form aluminium chloride and water, reducing stomach pH.

References

1. Anderson, C. Pharmacodynamics 2. ICU Primary Prep.
2. Law of Mass Action. Encyclopaedia Britannica.
3. ANZCA August/September 2001
4. Catterall WA. Structure and Function of Voltage-Gated Ion Channels. Annu. Rev. Biochem. 1995. 64:493-531.