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