GABA receptor

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GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.

StructureStructure

There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).

FunctionFunction

It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).

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ReferencesReferences

Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867. Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43. Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259. Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246. Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.