Editing GABAA receptor (section)

== Target for benzodiazepines ==
The [[ionotropic]] GABA<sub>A</sub> receptor protein complex is also the molecular target of the [[benzodiazepine]] class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor ''site'' on the protein complex as does the endogenous ligand [[Gamma-aminobutyric acid|GABA]] (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABA<sub>A</sub> receptors.<ref name="pmid12171574">{{cite journal | vauthors = Sigel E | title = Mapping of the benzodiazepine recognition site on GABA(A) receptors | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 8 | pages = 833–9 | date = August 2002 | pmid = 12171574 | doi = 10.2174/1568026023393444 }}</ref><ref name="pmid15530567">{{cite book | vauthors = Akabas MH | title = GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures | volume = 62 | pages = 1–43 | year = 2004 | pmid = 15530567 | doi = 10.1016/S0074-7742(04)62001-0 | isbn = 978-0-12-366862-2 | series = International Review of Neurobiology }}</ref> While the majority of GABA<sub>A</sub> receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABA<sub>A</sub> receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines,<ref name="pmid15009644">{{cite journal | vauthors = Derry JM, Dunn SM, Davies M | title = Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding | journal = Journal of Neurochemistry | volume = 88 | issue = 6 | pages = 1431–8 | date = March 2004 | pmid = 15009644 | doi = 10.1046/j.1471-4159.2003.02264.x | doi-access =  | s2cid = 83817337 }}</ref> but instead are sensitive to other classes of GABAergic drugs such as [[neurosteroid]]s and alcohol. In addition [[translocator protein|peripheral benzodiazepine receptors]] exist which are not associated with GABA<sub>A</sub> receptors. As a result, the [[International Union of Basic and Clinical Pharmacology|IUPHAR]] has recommended that the terms "''BZ receptor''", "''GABA/BZ receptor''" and "''omega receptor''" no longer be used and that the term "''benzodiazepine receptor''" be replaced with "'''benzodiazepine site'''".<ref name="pmid9647870">{{cite journal | vauthors = Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ | 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 | doi = 10.1016/S0031-6997(24)01363-2 | pmid = 9647870 | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/291 | archive-date = 2009-03-14 | access-date = 2008-06-20 | archive-url = https://web.archive.org/web/20090314082829/http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/291 | url-status = dead | url-access = subscription }}</ref> Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABA<sub>A</sub> receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.<ref>{{cite journal |vauthors=Gidal B, Detyniecki K |title=Rescue therapies for seizure clusters: Pharmacology and target of treatments |journal=Epilepsia |volume=63 |issue=Suppl 1 |pages=S34–S44 |date=September 2022 |pmid=35999174 |pmc=9543841 |doi=10.1111/epi.17341 }}</ref>

In order for GABA<sub>A</sub> receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA<sub>A</sub> receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA<sub>A</sub> receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.<ref name="pmid30044221">{{cite journal | vauthors = Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E | title = Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABA<sub>A</sub> 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>

Different benzodiazepines have different affinities for GABA<sub>A</sub> receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with [[sedation]], [[ataxia]] and [[amnesia]], whereas those with higher activity at GABA<sub>A</sub> receptors containing α2 and/or α3 subunits generally have greater [[anxiolytic]] activity.<ref>{{cite journal | vauthors = Atack JR | title = Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 2 | issue = 4 | pages = 213–232 | date = August 2003 | pmid = 12871032 | doi = 10.2174/1568007033482841 }}</ref> [[Anticonvulsant]] effects can be produced by agonists acting at any of the GABA<sub>A</sub> subtypes, but current research in this area is focused mainly on producing α<sub>2</sub>-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

The binding site for benzodiazepines is distinct from the binding site for [[barbiturates]] and GABA on the GABA<sub>A</sub> receptor, and also produces different effects on binding,<ref name="pmid18367615">{{cite journal | vauthors = Hanson SM, Czajkowski C | title = Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor | journal = The Journal of Neuroscience | volume = 28 | issue = 13 | pages = 3490–9 | date = March 2008 | pmid = 18367615 | pmc = 2410040 | doi = 10.1523/JNEUROSCI.5727-07.2008 }}</ref> with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.<ref name="pmid2471436">{{cite journal | vauthors = Twyman RE, Rogers CJ, Macdonald RL | title = Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital | journal = Annals of Neurology | volume = 25 | issue = 3 | pages = 213–220 | date = March 1989 | pmid = 2471436 | doi = 10.1002/ana.410250302 | hdl = 2027.42/50330 | s2cid = 72023197 | hdl-access = free }}</ref> Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.<ref>{{cite journal |vauthors=Hanson SM, Czajkowski C |title=Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor |journal=J Neurosci |volume=28 |issue=13 |pages=3490–9 |date=March 2008 |pmid=18367615 |pmc=2410040 |doi=10.1523/JNEUROSCI.5727-07.2008 }}</ref>

Also note that some GABA<sub>A</sub> agonists such as [[muscimol]] and [[gaboxadol]] do bind to the same site on the GABA<sub>A</sub> receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.