More than 50 years ago g-Aminobutyric acid was regards as a potentially important brain chemical, but its significance as a neurotransmitter was not totally found until over 30 years later. GABA had been put up as early as 1910. In 1954, Kuffler and Florey described the presence of excitatory and inhibitory control mechanisms in crustacea. Later, Florey and McLennan found GABA in mammiferous brain and considered that it may the natural neurotransmitter. Curtis and colleagues noted that strychnine failed to block the effects of GABA in the spinal cord. In 1968, Curtis and colleagues' findings was resolved by Krnjevic and Schwartz on cerebral cortical neurons and provided unequivocal evidence for GABA as an inhibitory transmitter. In 1978, Barber RP  were able to describe the distribution of the forming enzyme for GABA in the mammalian spinal cord and they considered that bicuculline can block the action of GABA. In 1980, Bowery  argued that GABA and baclofen could inhibit the K+ evoked release of neurotransmitter from brain slices. they found that the novel recepor was different from GABA-A receptors. In 1981, they called the novel receptor "GABA-B". In 1988, Roger Nicoll found that GABA-B receptors are sensitive not to K+ channels but to Ca2+ channels.
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Earlier in 1960s , Curtis and Werman reported that the action of potential firing in spinal neurones was reduced by glycine. After ten years , Hopkin and Neal  found that they can detect the release of amino acid after applying stimulation., but they failed to name the amino acid. In 1973 Young and Snyder revealed that the higher concentrations of strychnine can block the amino acid. In 1982, Pfeiffer  and colleagues separated and purified the amino acid from the adult rats spinal postsynaptic membrane and then they named it glycine receptor . In 1983, Graham  reported that 3H-strychnine could bind irreversibly the glycine receptor if it was exposed to UV light. Their discovery provided the possible method to isolate the glycine receptor biochemically
1.3 GABA receptor structure
1.3.1 GABA-A receptor: GABA-A receptor is embedded in the nerve cell membranes. Benzodiazepines and Barbiturate can be corresponding with the GABA-A receptor by changing the conformation of the receptor complex and enhance the effection of the GABA-A receptor. GABA-A receptor in the mammalian is pentamer molecules and consists of 5 subunits. , which in the centre of molecules is the channel of chloride. GABAA receptor consists of five subunits(2Î±ã€2Î²ã€1Î³) arranged pseudosymmetrically around a central pore. The predominant form of the receptor in the brain is composed of Î±1Î²2Î³2 subunits. Each subunit is compose of 400 to 550 amino acid residues, whose N-terminal pro waters is consist of approximately 220 amino acid at the end of subunits and have four hydrophobic transmembrane region. Length of each sequence of 22 amino acid residues between transmembrane sequence is linked by hydrophilic amino acids. a conserved praline in the center of the common sequence acts as a important role in the formation of receptor channel and the role of gating and barbiturates. Moreover , the back pack in the Î² structure of TM1 has the effect on the adjacent TM2. The formation of hydrophilic amino acid chloride channels, can selective to the negatively chloride ions. BZ sites on GABAA receptor binding can increase the frequency of chloride channel opening and Barbiturates at low concentrations enhance the effect of GABA receptor binding and increase the mean open time of chloride channel. However, Barbiturates at high concentrations can directly activate chloride channels without GABA.
1.3.2 GABAB receptor.: GABA-B receptor has seven transmembrane domain, which C terminal is located in the extracellular, N terminal in the intracellular . GABA-B receptor is composed of GABAB1 and GABAB2. GABAB1 is heterodimer which link its C-termin with polypeptide chain which exist in R2 . The structure of GABAB1 is similar with GABAB2, especially extracellular N2-long-chain . The molecular of GABAB2 weight is 110 00, which have seven transmembrane domain. The single GABAB2 can form functional site, but lack binding site. A fully functional GABAB receptor must be consist of GABAB1 and GABAB2.
GABAB receptor is not an typical member of class-C G protein coupled receptor family which is heterodimerized by GABAB1 and GABAB2 subunits and the two subunits convey specific and different components during activation. GABAB receptors couple to Ca21 and K1 channels via G proteins and second messenger systems. In presynaptic, Ca+2 channels is divided into the N-type ã€P- typeã€ L -typeã€T-typeã€R-type or Q-type. GABAB receptor is voltage-dependent inhibition of voltage-gate Ca+2 , which cause presynaptic inhibition of elicited neurotransmitter release. So GABAB receptors block Ca+2 influx by inhibiting Ca+2 channels in a membrane-delimited manner by the GÎ²Î³ subunits. On the postsynaptic, GABAB receptors lead to a slow inhibitory current via activation of inwardly rectifying K+ channels. Therefore, IPSCs can be inhibited by the Kir3 channel blocker Ba2 and they usually display a opposite potential similar to the K_ equilibrium potential. The physiological effect of Kir3- channel activation is normally a K outflow, which cause hyperpolarization.
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1.3.3 GABAC receptor: GABAC receptor is composed of five subunits pentamerï¼Œin middle of which is the CI- channel. Each subunits pentamer form four transmembran domain(TM). There is a large extracellular N-terminal domain outside the cellï¼Œintracellular cyclic between the third and fourth transmembran domain and extracellular C-terminal domain behind the fourth transmembran domain. extracellular N-terminal domain contain the ligand and a variety of regulator binding sites,which contain a conservative Cys-Cys ring. 5 subunits form a channel, which is a selective permeability to cl-
pl subunit is the main formation of GABAC receptor, which is first loned in the retinal. GABAC receptor is pentamer of homologous formed by the pl subunit as well as heterologous pentamer formed by the pl and p2 subunit. p2 can not form a single homologous pentamer, only when p2 and pl together form a functional channel. because the pl subunit assembly has a unique motif. 70 amino acids in the N terminal of the pl subunit is important for assembly of sequence homology in the pl subunit, which does not play a role with p2. pl subunit in the brain and spinal cord can bind to GABAA receptor subunit and assemble into a new receptor. So GABAC receptor / channel that consists of pl subunits is more sensitive to the GABA and also has a more lasting channel opening timeand the desensitization of GABAC Receptor does not show obvious, which is not regulated by Benzodiazepine ã€neural steroid compounds and barbiturates.
1.3.4 Glycine receptor: two juxtaposed a1 subunits of the glycine receptor base on a homology model with the acetylcholine-binding protein and the TM domains taken from the nicotinic acetylcholine receptor. The N-terminal domains are shown in blue with the Cys loops depicted in yellow. The TM domains TM1, 3 and 4 are shown in green and the ion channel lining TM2 is shown in orange. The model illustrates the position of histidines 107 and 109 (orange) and their ability to coordinate a Zn+ ion (red) at the interface between two adjacent a1 subunits. The alignments were generated using DeepView version 3.7
ï¼ˆfromï¼šKuhse J , Betz H , Kirsch J . The inhibitory glycine receptor :architecutre , synaptic localization and molecular pathology of a postsynaptic ion2channel complex. Curr Opin Neurobiol , 1995 , 5(3) : 318ï½ž323ï¼‰
1.4 the biological function of GABA receptor
Î³-aminobutyric acid (Î³-aminobutiric acid,GABA) is an important inhibitory neurotransmitter in the central nervous system and peripheral nervous system , which plays the physiological function by ionic Channels (GABAA GABAC) receptors and metabotropic (GABAB) receptors. â‘ GABAA receptors is the major inhibitory receptors in central nervous system , which would lead to membrane Cl - channel opening. Barbiturates and the benzodiazepine are acting on GABAA receptor and resulting in the effect of sedative, hypnotic, anticonvulsant.In most condition, due to lower intracellular Cl - ion concentrations, Cl - will enter the cell visa the concentration difference and result in the increase of intracellular membrane potential and hyperpolarization and inhibit neuronal excitability. So GABAA receptor mediates inhibitory postsynaptic currents.however in the development of neurons, astrocytes , intracellular Cl - concentration flow out of the cell and result in depolarization. â‘¡ GABAB[18,19] receptors in the the central nerve system may be related to esthesia, whose agonists inhibite the release substance P, glutamate and calcitonin gene-related peptide (CGRP) in the spinal cord. These substances are considered to be sensory transmitter, located in the spinal cord dorsal horn of the afferent nerve endings. GABAB receptors in the rostral ventrolateral (RVLM) regulate the cardiovascular activit.vsome research suggest that blood pressure, heart rate may be high in the condition of inject inglow-dose of GABAB receptor antagonist into RVLM. The mechanism may be that K + channels is opened by Gi inducing hyperpolarization of postsynaptic membrane and result in slow inhibitory postsynaptic potentials. Or The other mechanism may be that Ca+2 channels on the presynaptic may be blocked by Gi protein, resulting in reducing the release of excitatory neurotransmitters and causing presynaptic inhibition.the research in the development of individual suggests that GABAB1a may be at a high rate in the earlier five day of newborn mice and return to normal level after two weeks. The expression of GABAB1b may go up five day after birth and reach the peak at ten days. At the beginning of newborn mice ,the GABAB1a is five times to GABAB1b. two weeks later , the expression of GABAB1b and GABAB1a are equal . in sum, in the development of brain GABAB1 at birth tends to decrease , which may change into the expression of GABAB2 in adulthood. â‘¢ Several studys indicate that GABAC receptors are composed of p1 or p2 subunits in humansã€‚GABAC receptor cells have been shown to inhibit the release of neurotransmitters in axon terminals. GABAC receptors are integral membrane ion channels, which stabilize the resting potential of cells through regulating the chloride ions. GABAC can show its function of inhibition under the low concentrations of GABA, which is longer than the inhibition of GABAA receptor. When the concentration of GABA transporter in Synaptic cleft reduce to a certain value, GABA A receptors have been unable to bear the intensity of the inhibition and the role of GABAC receptor became very important. So compare to GABAA receptor ,GABAC receptor has some advanctage : higher sensitivity to GABA and longer opening times and sustained currents with a slower onset. In sum , GABAC receptors would activate at lower GABA concentrations with a prolonged response compared with GABAA receptors. Besides, Hippocampus is responsible for learning and memory and GABAC receptors which is in Hippocampus on learning and memory may also have a vital role of regulatory.
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the biological function of Glycine receptor
Glycine[21,22] is is an oligomeric ï¼Œwhich is recognized as the major inhibitory neurotransmitter in the spinal cord. glycoprotein forms a transmembrane channel ,which is selective to chloride ions. Once glycine combines with the glycine receptor, the pore of cell opens allowing Cl- passively diffuse across the membrane. The Cl- conductance results in the hyperpolarization of neuron and preventing depolarization and inducing neuronal firing by excitatory neurotransmitters. In the brain stem and medulla of mammalian the glycine mediated inhibitory transmission is essential for the voluntary motor control as well as for generation of reflex responses.Besides Glycine is a major inhibitory neurotransmitter in the adult CNS, it is excitatory neurotransmitter during embryonic development and around birth . In the times of the developing CNS, the intracellular Cl- concentration is increased in comparison with the extracellular medium. So the activation of Glycine induces outflow of Cl-, resulting in a fierce depolarization and neurotransmitter release instead of hyperpolarization. Glycine receptor lead to Ca2+rises in intracellular,which is vital to the correct formation of postsynaptic glycinergic membrane specializations.
In short , GABA receptor and Glycine receptor have several physiological functions in CNS. Previous studies provide important theoretical and demonstrated broad clinical application to us. therefore We should continue to strengthen the research on GABA receptor and Glycine receptor.