Inhibitory amino acids
GABA
GABA (γ aminobutyric acid) is widely used throughout the CNS - virtually every neurone will be inhibited by it. It is mainly contained in short inhibitory interneurones. GABAAreceptors are a major site of drug action, particularly for sedatives, anticonvulsants and general anaesthetics. GABAAreceptors are also present on peripheral neurones but what they do there is not obvious. The GABAAreceptor is a ligand gated ion channel which opens when two molecules of GABA bind to it which causes chloride ions to flow into the cell, causing hyperpolarisation and thus inhibiting firing. Blockade of the chloride channel by experimental drugs and toxins causes convulsions.
As well as binding GABA, GABAA receptors also bind benzodiazepines (sedatives) and, less strongly, barbiturates (injectable anaesthetics). Both classes of drugs potentiate the effects of GABA by various means and cause postsynaptic inhibition. GABAAreceptors are probably also the site of action of most anaesthetic agents. Some drugs also bind to the benzodiazepine receptor to stop the channel opening (inverse agonists - do not confuse with benzodiazepine antagonists which only block the effects of benzodiazepines and have no effect on their own). Endogenous inverse agonists are thought to exist but their function is unknown - exogenous ones make animals anxious which is not usually desirable.
The GABAA receptor is composed of five subunits, but 19 different subunits have been cloned and there are probably 500 subtypes of GABAAreceptors. Drugs specific for these subtypes are likely to emerge. The use of knockout mice has led to the discovery of the probable involvement of α1 and β2 subunits in sedation, of α2 in anxiety and myorelaxation, of α5 in learning, of β3 in anaesthesia, of δ in epileptic seizures etc.
GABABreceptors have a presynaptic inhibitory action and may be important in the spinal cord but not much is known about their function. They are G protein coupled receptors. There are probably lots of different subtypes. GABACreceptors are chloride channels similar to GABAAreceptors; they have been studied in the retina but are probably more widely distributed. So far, their function seems to be the same as GABAA receptors.
Glycine
Glycine is also an important inhibitory transmitter, particularly in the spinal cord. It binds to a chloride channel receptor very similar to the GABAA receptor (ie, different from the glycine receptor associated with the NMDA receptor). This is clinically important as strychnine is a competitive antagonist at the glycine inhibitory receptor - in strychnine poisoning, an animal will start to twitch. Tetanus toxin blocks the release of glycine (and GABA) resulting in continuous muscle contraction.
Both the GABA and glycine gated chloride channels are similar
to the glutamate gated chloride channels found in invertebrates and which are
the target for avermectin parasiticides. In overdose, these commonly used drugs
can open GABA and glycine gated chloride channels to cause CNS inhibitory effects
in mammals. Avermectins do not usually get into mammalian brains because the
P glycoprotein pump in the blood brain barier keeps them out. Some individual
animals (particularly collies) are missing the gene for the P glycoprotein and
will go into a prolonged coma if given avermectins.
The GABAA receptor. GA = general anaesthetic binding site, BDZ = benzodiazepine binding site.
