3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.1. Pharmacology principles
                      3.1.3.1.2. Pharmacodynamics
                          3.1.3.1.2.2. Mechanism of drug actions
 3.1.3.1.2.2.1. Receptors 

Receptors

[PHW2:p4; SH4:p19-21; RD5:p26-45]

Receptors are of 4 types:

  • Transmembrane
    * Ligand-gated ion channels
    * G-protein-coupled receptors
    * Kinase-linked receptors
  • Intracellular

1. Ligand-gated ion channels

  • aka ionotropic receptors
  • Binding of ligand to the receptor
    --> Associated ion channels open (without invovlement of a second messenger)
  • Pentameric receptors (??? 5 subunits)
    * Each subunit has 4 transmembrane segments
    * [SH:p36]
  • Some ligand-gated ion channels are activated by intracellular mediators [RD5:p46]
    * e.g. Ca2+ activated K+ channels open when intracellular Ca2+ concentration increases
    * e.g. ATP-sensitivie K+ channels open when intracellular ATP concentration falls

Examples:

  • Nicotinic acetylcholine receptors
  • Gamma-aminobutyric acid type A (GABAa)
  • Glutamate receptors of NMDA, AMPA, and kainate types

NB:

  • AMPA = Alpha-amino-3-hydroxy-5-methyl-4-isooxazolepropionate
  • NMDA = N-methyl-D-aspartate

Ligand-gated ion channels consist of two families

Two families:
* Specific neurotransmitters
* Ligand-gated glutamate receptors

1.1. Specific neurotransmitters

  • Excitatory, cation-selelctive
    * Nicotinic acetylcholine receptor (nAch)
    * Serotonin receptor (5HT3)
  • Inhibitory, anion-selective
    * Gamma-aminobutyric acid receptor (GABAa)
    * Glycine receptors
1.1.1. Acetylcholine (ACh) receptor
  • Pentameric (2 alpha, 1 beta, 1 delta, and 1 gamma subunits)
  • Ligand-gated channel
    * Ligand = Ach
    * Channel = Small cations, e.g. Na+
  • Binding of acetylcholine to each of the two alpha subunits
    --> Opening of the ion channel
    --> Outflow of K+
    --> Hyperpolarisation
  • Also bind to neuromuscular blocking drugs, and anticholinergic drugs
1.1.2. GABAa receptor

[GABA receptors]

  • Pentameric (5 subunits)
  • Ligand-gated channel
    * Ligand = GABA
    * Channel = Anions, especially Cl-
  • Binding of GABA
    --> Opening of the ion channel
    --> Inflow of Cl-
    --> Hyperpolarisation
  • Also activated by
    * Benzodiazepines
    * Barbiturates
    * Propofol
    * Volatile anaesthetics
    * Metabolites of progesterone and deoxycorticosterone [WG21:p112]
  • Propofol and barbiturates decrease the rate of dissociation of GABA from GABAa receptors
    --> Duration of Cl- channel opening is prolonged [SH4:p128]
  • Barbiturate may also mimic action of GABA and directly activate GABAa receptors [SH4:p128]
Anaesthetic and GABAa receptors
  • Complete anaesthetic cannot be provided by GABAa-agonist actions of hypnotic drugs
    * e.g. benzodiazepines, barbiturates, propofol, etomidate
  • Opioids and alpha2 agonists inhibits presynaptic calcium ion channel
    * Responsible for neurotransmitter release

Thus,

  • Combination of activation of GABAa and inhibition of presynaptic calcium channel
    --> Full anaesthetics
  • Volatile anaesthetics may provide both
1.1.3. 5-Hydroxytryptamine (5-HT) receptors

Subtypes

  • 5HT3 subtype is ligand-gated
    * Na+ channel [WG21:p99]
  • All other subtypes are metabotropic (i.e. G-protein coupled)

Properties

  • Excitatory
  • Selectively permeable to cations
  • Actions in CNS include anxiolysis, analgesia, and emetic
1.1.4. Glycine receptors
  • Glycine receptors are closely related to GABAa receptors
  • Inhibitory
  • Mainly in spinal cord
  • Activity is enhanced by volatile anaesthetics
  • Tetanus toxin acts selectively to prevent glycine release from inhibitory interneurons in the spinal cord
    --> Excessive hyperexcitability and violent muscle spasms (lockjaw)
    * [RD5:p473]

1.2. Ligand-gated glutamate receptors

4 types of glutamate receptors

  • Ligand-gated types (i.e. ionotropic)
    * N-methyl-D-aspartate (NMDA)
    * Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
    * Kainate
  • Metabotropic
    * Involves G-protein (i.e. NOT ligand-gated)
    * Also has 7 transmembrane segments
Glutamate vs GABA
  • Glutamate is the principle excitatory neurotransmitter in CNS
    * Cannot cross BBB --> Must originate from local metabolism
  • GABA is the primary inhibitory neurotransmitter in CNS
    * Responsible for most fast synaptic inhibition of neurons
    * 1/3 of all synapses in CNS respond to GABA
    * Cannot cross BBB --> Can't be administered systemically

2. G-protein-coupled receptors (GPCRs)

See [G-protein system]

  • aka metabotropic receptors
  • Coupled to intracellular effector system via a G-protein
    * Called G-protein because of their interaction with guanine nucleotides GTP and GDP
  • Consisting of 7 transmembrane segments

 

Examples include:

  • Muscarinic ACh receptors
  • Adrenoceptors
  • Opiate receptors
  • Dopamine receptors
  • Adenosine receptors
  • 5-HT receptors (except for 5-HT3)

3. Kinase-linked receptors

  • A large extracellular ligand-binding domain, linked to an intracellular domain by a single transmembrane helix
  • Often the intracellular domain is enzymic
    * e.g. protein kinase (tyrosine kinase), guanylate cyclase (less common)
  • Two important pathways [RD5:p42]
    * Ras/Raf/MAP kinase pathway = Important in cell division, growth, and differentiation
    * Jak/Stat pathway = Controls the synthesis and release of many inflammatory mediators

 

Examples include:

  • Receptors for insulin, cytokines, and growth factors are the protein kinase type (??? all three are tyrosine kinase)
  • Receptor for atrial natriuretic factors (ANF) is the main example for the guanylate cyclase type

4. Intracellular receptors

  • Most receptors are located in the nucleus
  • Ligands are all lipophilic compounds
  • Binding of the ligand to the receptor
    --> Changes in RNA polymerase activity and changes in mRNA production

 

Examples include:

  • Steroid
  • Thyroid hormone
  • Vitamin D
  • Retinoic acid