Editing GABA receptor (section)

===GABA<sub>A</sub> receptor===
{{Main|GABAA receptor}}

It has long been recognized that, for neurons that are stimulated by [[bicuculline]] and [[picrotoxin]], the fast inhibitory response to GABA is due to direct activation of an [[anion]] channel.<ref name="Kuffler">{{cite journal | vauthors = Kuffler SW, Edwards C | title = Mechanism of gamma aminobutyric acid (GABA) action and its relation to synaptic inhibition | journal = Journal of Neurophysiology | volume = 21 | issue = 6 | pages = 589–610 | date = November 1958 | pmid = 13599049 | doi = 10.1152/jn.1958.21.6.589 | url = http://jn.physiology.org/cgi/citmgr?gca=jn;21/6/589 | url-status = dead | archive-url = https://web.archive.org/web/20040803162301/http://jn.physiology.org/cgi/citmgr?gca=jn | archive-date = 2004-08-03 | url-access = subscription }}</ref><ref name="Kravitz">{{cite journal | vauthors = Kravitz EA, Kuffler SW, Potter DD | title = Gamma-Aminobutyric Acid and Other Blocking Compounds in Crustacea: III. Their Relative Concentrations in Separated Motor and Inhibitory Axons | journal = Journal of Neurophysiology | volume = 26 | pages = 739–51 | date = September 1963 | issue = 5 | pmid = 14065325 | doi = 10.1152/jn.1963.26.5.739 }}</ref><ref name="Krnjevic">{{cite journal | vauthors = Krnjević K, Schwartz S | title = The action of gamma-aminobutyric acid on cortical neurones | journal = Experimental Brain Research | volume = 3 | issue = 4 | pages = 320–36 | year = 1967 | pmid = 6031164 | doi = 10.1007/BF00237558 | s2cid = 6891616 }}</ref><ref name="Takeuchi1967">{{cite journal | vauthors = Takeuchi A, Takeuchi N | title = Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction | journal = The Journal of Physiology | volume = 191 | issue = 3 | pages = 575–90 | date = August 1967 | pmid = 6051794 | pmc = 1365493 | doi = 10.1113/jphysiol.1967.sp008269 }}</ref><ref name="pmid5357245">{{cite journal | vauthors = Takeuchi A, Takeuchi N | title = A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish | journal = The Journal of Physiology | volume = 205 | issue = 2 | pages = 377–91 | date = November 1969 | pmid = 5357245 | pmc = 1348609 | doi = 10.1113/jphysiol.1969.sp008972 }}</ref> This channel was subsequently termed the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="pmid4502428">{{cite journal | vauthors = Takeuchi A, Onodera K | title = Effect of bicuculline on the GABA receptor of the crayfish neuromuscular junction | journal = Nature | volume = 236 | issue = 63 | pages = 55–6 | date = March 1972 | pmid = 4502428 | doi = 10.1038/236055a0 | s2cid = 12978932 | doi-access = free }}</ref> Fast-responding GABA receptors are members of a family of [[Cys-loop]] [[Ligand-gated ion channel|ligand-gated]] [[ion channels]].<ref name="Barnard">{{cite journal | vauthors = Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ | display-authors = 6 | title = International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function | journal = Pharmacological Reviews | volume = 50 | issue = 2 | pages = 291–313 | date = June 1998 | pmid = 9647870 | url = http://pharmrev.aspetjournals.org/cgi/content/full/50/2/291 }}</ref><ref name="Hevers">{{cite journal | vauthors = Hevers W, Lüddens H | title = The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes | journal = Molecular Neurobiology | volume = 18 | issue = 1 | pages = 35–86 | date = August 1998 | pmid = 9824848 | doi = 10.1007/BF02741459 | s2cid = 32359279 }}</ref><ref name="Sieghart">{{cite journal | vauthors = Sieghart W, Sperk G | title = Subunit composition, distribution and function of GABA(A) receptor subtypes | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 8 | pages = 795–816 | date = August 2002 | pmid = 12171572 | doi = 10.2174/1568026023393507 }}</ref> Members of this superfamily, which includes [[nicotinic acetylcholine receptor]]s, GABA<sub>A</sub> receptors, [[Glycine receptor|glycine]] and [[5-HT3|5-HT<sub>3</sub>]] receptors, possess a characteristic loop formed by a [[disulfide bond]] between two [[cysteine]] residues.<ref>{{cite journal | vauthors = Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E | title = A receptor in complex with GABA | journal = eLife | volume = 7 | pages = e39383 | date = July 2018 | pmid = 30044221 | pmc = 6086659 | doi = 10.7554/eLife.39383 | doi-access = free }}</ref>

In ionotropic GABA<sub>A</sub> receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a [[chloride ion]]-selective pore.<ref>{{cite journal | vauthors = Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E | title = A receptor in complex with GABA | journal = eLife | volume = 7 | pages = e39383 | date = July 2018 | pmid = 30044221 | pmc = 6086659 | doi = 10.7554/eLife.39383 | doi-access = free }}</ref> The increased chloride [[Electrical conductance|conductance]] drives the [[membrane potential]] towards the reversal potential of the Cl¯ ion which is about –75 [[Volt|mV]] in neurons, inhibiting the firing of new [[action potential]]s. This mechanism is responsible for the [[sedative]] effects of GABA<sub>A</sub> allosteric agonists. In addition, activation of GABA receptors lead to the so-called [[shunting inhibition]], which reduces the excitability of the cell independent of the changes in membrane potential.

There have been numerous reports of excitatory GABA<sub>A</sub> receptors. According to the excitatory GABA theory, this phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system<ref name="pmid9364667">{{cite journal |vauthors=Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL | title = GABAA, NMDA and AMPA receptors: a developmentally regulated 'ménage à trois' | journal = Trends Neurosci. | volume = 20 | issue = 11 | pages = 523–9 |date=November 1997 | pmid = 9364667 | doi = 10.1016/S0166-2236(97)01147-8  | s2cid = 8022055 }}</ref><ref name="pmid10717431">{{cite journal |vauthors=Taketo M, Yoshioka T | title = Developmental change of GABA(A) receptor-mediated current in rat hippocampus | journal = Neuroscience | volume = 96 | issue = 3 | pages = 507–14 | year = 2000 | pmid = 10717431 | doi = 10.1016/S0306-4522(99)00574-6  | s2cid = 22103661 }}</ref> or in certain cell populations.<ref name=Tomiko>{{cite journal |vauthors=Tomiko SA, Taraskevich PS, Douglas WW | title = GABA acts directly on cells of pituitary pars intermedia to alter hormone output | journal = Nature | volume = 301 | issue = 5902 | pages = 706–7 |date=February 1983 | pmid = 6828152 | doi = 10.1038/301706a0  | bibcode = 1983Natur.301..706T | s2cid = 4326183 }}</ref><ref name=Cherubini>{{cite journal |vauthors=Cherubini E, Gaiarsa JL, Ben-Ari Y |title=GABA: an excitatory transmitter in early postnatal life |journal=Trends Neurosci. |volume=14 |issue=12 |pages=515–9 |date=December 1991 | pmid = 1726341 | doi =  10.1016/0166-2236(91)90003-D |s2cid=3971981 }}</ref><ref name=Lamsa>{{cite journal |vauthors=Lamsa K, Taira T | s2cid = 17650510 | title = Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area | journal = J. Neurophysiol. | volume=90 |issue = 3 | pages = 1983–95 |date=September 2003 | pmid = 12750426 | doi = 10.1152/jn.00060.2003  }}</ref> After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl<sup>−</sup> ions into the extracellular space of the tissue. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and [[IPSP|inhibitory postsynaptic potential]]s are no longer relevant.

However, the excitatory GABA theory has been questioned as potentially being an artefact of experimental conditions, with most data acquired in in-vitro brain slice experiments susceptible to un-physiological milieu such as deficient energy metabolism and neuronal damage. The controversy arose when a number of studies have shown that GABA in neonatal brain slices becomes inhibitory if glucose in perfusate is supplemented with ketone bodies, pyruvate, or lactate,<ref>{{cite journal | vauthors = Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y | title = GABA action in immature neocortical neurons directly depends on the availability of ketone bodies | journal = Journal of Neurochemistry | volume = 110 | issue = 4 | pages = 1330–8 | date = August 2009 | pmid = 19558450 | doi = 10.1111/j.1471-4159.2009.06230.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y | title = Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro | journal = Journal of Neurochemistry | volume = 112 | issue = 4 | pages = 900–12 | date = February 2010 | pmid = 19943846 | doi = 10.1111/j.1471-4159.2009.06506.x | doi-access = free }}</ref> or that the excitatory GABA was an artefact of neuronal damage.<ref>{{cite journal | vauthors = Dzhala V, Valeeva G, Glykys J, Khazipov R, Staley K | title = Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain | journal = The Journal of Neuroscience | volume = 32 | issue = 12 | pages = 4017–31 | date = March 2012 | pmid = 22442068 | pmc = 3333790 | doi = 10.1523/JNEUROSCI.5139-11.2012 }}</ref> Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results,<ref>{{cite journal | vauthors = Kirmse K, Witte OW, Holthoff K | title = GABA depolarizes immature neocortical neurons in the presence of the ketone body β-hydroxybutyrate | journal = The Journal of Neuroscience | volume = 30 | issue = 47 | pages = 16002–7 | date = November 2010 | pmid = 21106838 | pmc = 6633760 | doi = 10.1523/JNEUROSCI.2534-10.2010 }}</ref><ref>{{cite journal | vauthors = Ruusuvuori E, Kirilkin I, Pandya N, Kaila K | title = Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism | journal = The Journal of Neuroscience | volume = 30 | issue = 46 | pages = 15638–42 | date = November 2010 | pmid = 21084619 | pmc = 6633692 | doi = 10.1523/JNEUROSCI.3355-10.2010 }}</ref><ref>{{cite journal | vauthors = Tyzio R, Allene C, Nardou R, Picardo MA, Yamamoto S, Sivakumaran S, Caiati MD, Rheims S, Minlebaev M, Milh M, Ferré P, Khazipov R, Romette JL, Lorquin J, Cossart R, Khalilov I, Nehlig A, Cherubini E, Ben-Ari Y | display-authors = 6 | title = Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate | journal = The Journal of Neuroscience | volume = 31 | issue = 1 | pages = 34–45 | date = January 2011 | pmid = 21209187 | pmc = 6622726 | doi = 10.1523/JNEUROSCI.3314-10.2011 }}</ref> but the truth remained elusive until the real effects of GABA could be reliably elucidated in intact living brain. Since then, using technology such as in-vivo electrophysiology/imaging and optogenetics, two in-vivo studies have reported the effect of GABA on neonatal brain, and both have shown that GABA is indeed overall inhibitory, with its activation in the developing rodent brain not resulting in network activation,<ref>{{cite journal | vauthors = Kirmse K, Kummer M, Kovalchuk Y, Witte OW, Garaschuk O, Holthoff K | title = GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo | journal = Nature Communications | volume = 6 | pages = 7750 | date = July 2015 | pmid = 26177896 | doi = 10.1038/ncomms8750 | bibcode = 2015NatCo...6.7750K | doi-access = free }}</ref> and instead leading to a decrease of activity.<ref>{{cite journal | vauthors = Valeeva G, Tressard T, Mukhtarov M, Baude A, Khazipov R | title = An Optogenetic Approach for Investigation of Excitatory and Inhibitory Network GABA Actions in Mice Expressing Channelrhodopsin-2 in GABAergic Neurons | journal = The Journal of Neuroscience | volume = 36 | issue = 22 | pages = 5961–73 | date = June 2016 | pmid = 27251618 | pmc = 6601813 | doi = 10.1523/JNEUROSCI.3482-15.2016 }}</ref><ref>{{cite journal | vauthors = Zilberter M | title = Reality of Inhibitory GABA in Neonatal Brain: Time to Rewrite the Textbooks? | journal = The Journal of Neuroscience | volume = 36 | issue = 40 | pages = 10242–10244 | date = October 2016 | pmid = 27707962 | pmc = 6705588 | doi = 10.1523/JNEUROSCI.2270-16.2016 }}</ref>

GABA receptors influence neural function by coordinating with glutamatergic processes.<ref>{{cite journal | vauthors = Farahmandfar M, Akbarabadi A, Bakhtazad A, Zarrindast MR | title = Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice | journal = Neuroscience | volume = 344 | pages = 48–55 | date = March 2017 | pmid = 26944606 | doi = 10.1016/j.neuroscience.2016.02.056 | s2cid = 24077379 }}</ref>