Glycine and GA

Question 1

Where does glycine bind?

Answer 1

Strychnine-sensitive glycine receptors

Question 2

Describe the strychnine sensitive glycine receptor

Answer 2

Anion selective transmitter gated ion channel, closely related to the GABAAR family

More restricted expression in the CNS than GABAARs - spinal cord, brain stem, cerebellum and DRN

Question 3

What does the strychnine sensitive glycine receptors regulate?

Answer 3

Resp rhythms
Motor control
Muscle tone
Sensory and pain processing

Question 4

Describe the pharmacologically relevant binding sites on the glycine receptor

Answer 4

Glycine, taurine, strychnine (competitive antagonist)
Propofol (GABA modulator, 10 fold higher will influence function of glycine)
Isoflurane (enhances GABA, but will also enhance glycine)
Ethanol (enhances glycine receptors much more convincingly than GABAA)

Question 5

Describe strychnine

Answer 5

Obtained from the poisonous nuts of the strychnine tree

Potent competitive antagonist at glycine receptor

Enhances perception of pain

Causes convulsions

Question 6

How is glycine transported?

Answer 6

VIAAT; vesicle inhibitory amino acid transporter

GlyT1 astrocytic glycine transporter present on astrocytes
GlyT2 neuronal glycine transporter; back into neurons

Question 7

Describe the structure of the glycine receptor

Answer 7

Transmitter gated cys loop chloride conducting ion channel

Glycine; alpha 1-4, beta 1

Large extracellular N terminal
TM1,2,3,4
Extracellular carboxyl tail
TM2 = forms lining of anion channel

Question 8

Describe inhalational GA

Answer 8

Take a few mins to act and cause a period of excitement before anaesthesia

IV drugs are far quicker (propofol, etomidate, thiopental) to produce unconsciousness therefore are normally used for induction

Inhalational agents (isoflurane, sevoflurane) usually used for maintenance anaesthesia (continuous propofol can also be used)

Isoflurane enhances GABAAR function and glycine receptor function

Question 9

Are glycine receptors a viable target for GA?

Answer 9

Glycine-evoked responses are not influences by the IV GA etomidate, alphaxalone, pentobarbitone
Propofol does enhance glycine however is required around 10x higher concentration than that for GABAA

However, volatile anaesthetics such as isoflurane and halothane enhance GABA and glycine at similar concentrations

Question 10

Describe the role of glycine receptors and volatile inhalational GA

Answer 10

Intrathecal strychnine to rats anaesthetised with halothane or isoflurane increases the requirement for additional isoflurane or halothane

Intrathecal glycine reduced the amount of isoflurane required to anaesthetise a rat

A “knock-in” mouse carrying a point mutation that blunts isoflurane enhancement of alpha 1 glycine receptors (Q266I) has little effect on the in vivo actions of isoflurane

Therefore glycine receptors are considered not to be a major effect of mediating volatile anaesthetics

Question 11

What is the MAC?

Answer 11

Minimum alveolar concentration of anaesthetic at 1 atmosphere required to produce immobility in 50% of subjects exposed to a noxious stimulus