GABA receptors

Gamma-amino butyric acid - Skeletal structure

GABA is the primary inhibitory neurotransmitter in the brain. Crudely, GABA is the function opposite of glutamate, the primary excitatory neurotransmitter in the brain. They have a close interrelationship with GABA even synthesized from glutamate (as a precursor) by glutamate decarboxylase (GAD).

There are two superfamilies of GABA receptor, GABA-A receptors and GABA-B receptors:-

GABA-A receptor
The GABA(A) receptor is an ionotropic ligand gated channel. Of the two families of receptor, it is by far the most understood and is a target of a huge number of drugs including those for anxiety and producing sedation. When the ligand receptor site is boud to endogenous GABA, the GABA-A ion channel opens conducts Cl- ions through its pore. The Cl- influx causes hyperpolarization (internal membrane environment more negative than normal and comparatively more polarized (or negative) to the external membrane environment). Hyperpolarization prevents the likelihood of action potential generation and has an inhibitory effect on neurotransmission because Na+ dependant voltage gated channels cannot open unless the internal environment reaches threshold potential which is unlikely with the internal Cl- concentration greater than at resting potential.

GABA-B receptors are metabotropic, heterodimeric G-protein coupled receptors. GABA or exogenous agonist binding triggers a cascade of activity involving G-protein activation culminating in hyperpolarization of the neuron where the axonal environment is even more negatively charged that at normal resting potential. Hyperpolarization makes Na+ voltage gated channels highly unlikely to open (they open at threshold when the neuronal membrane potential difference approaches polarization) thus action potential firing is inhibited. GABA-B receptors are particularly important because they inhibit neurotransmitter release on pre-synaptic neurons.

G-protein activation can result in a hyperpolarized enrivornment in three ways. Firstly, activation of K+ channels during resting membrane potential (depolarization) means an efflux of K+ ions occurs down its concentration gradient leaving the internal environment more negative than normal due to the negatively charged protein content. This may have an effect anywhere on a neuron interupting conduction.
Inhibition of neurotransmitter release occurs by inhibiting Ca2+ influx into the pre-synaptic neuron and reducing its conductance within the neuron. The hyperpolarization caused by K+ channel opening and K+ efflux inhibits the opening of voltage gated calcium channels (VDCC). Ca2+ ions are necessary as they act as signalling molecules for exocytosis by stimulating Ca2+ sensitive proteins on the surface of vesicles. Also, inhibition of adenyl cyclase reduces coversion of ATP to cAMP which in turn reduces Ca2+ conductance in the neuron

Recap video of transmission at synapses: