GABAB receptor

Receptor gama aminobuterne kiseline (GABA) B, 2
Identifikatori
Simbol	GABBR2
Alt. simboli	GPR51
Entrez	9568
HUGO	4507
OMIM	607340
RefSeq	NM_005458
UniProt	O75899
Drugi podaci
Lokus	Hromozom 9 q22.1-22.3

Receptor gama aminobuterne kiseline (GABA) B, 1
Identifikatori
Simbol	GABBR1
Entrez	2550
HUGO	4070
OMIM	603540
RefSeq	NM_021905
UniProt	Q9UBS5
Drugi podaci
Lokus	Hromozom 6 p21.3

GABA_B receptori (GABA_BR) su metabotropni transmembranski receptori za gama-aminobuternu kiselinu (GABA) koji su vezani putem G proteina za kalijumske kanale.^[1] Promena koncentracije kalijuma hiperpolarizuje ćeliju na kraju akcionog potencijala. GABA_B posredovana promena potencijala je -100 mV, to je znatno više od promene potencijala koju proizvodi GABA_A. GABA_B receptori su prisutni u centralnom i perifernom autonomnom nervnom sistemu.

Funkcije

Oni mogu da stimulišu otvaranje K⁺ kanala ćime se neuron približava ravnotežnom potencijalu K⁺ jona, te dolazi do popularizaciju neurona. Time se sprečava otvaranje natrijumovog kanala, dejstvo akcionog potencijala, i otvaranje VDCC kanala, te se zaustavlja otpuštanje neurotransmitera. GABA_B receptori se smatraju inhibitornim receptorima.

GABA_B receptori takođe mogu da umanje aktivnost adenilil ciklaze i da redukuju ćelijsku provodnost za Ca²⁺.

GABA_B receptori posreduju dejstvo etanola,^[2] i gama-hidroksibuterne kiseline (GHB).^[3]^[4] Nedavna istraživanja sugeriraju da ovi receptori imaju važnu ulogu u razvoju organizma.^[5]

Struktura

GABA_B receptori imaju sličnu strukturu sa metabotropnim glutamatnim receptorima.^[6] Poznata su dva podtipa receptora, GABA_B1 i GABA_B2,^[7]. Oni se javljaju kao heterodimeri u neuronskim membranama. Do dimerizacije dolazi putem formiranja nevezujućih interakcija njihovih intracelularnih C terminusa.^[6]

Smatra se da vezivanje liganda uzrokuje znatnu konformacionu promenu aktivnog mesta.

Selektivni ligandi

GABA

GHB

Lezogaberan

Agonisti

GABA
Baklofen je GABA analog koji deluje kao selektivni agonist GABA_B receptora, i koristi se kao relaksant mišića.
Gama-hidroksibutirat (GHB)
Fenibut
3-Aminopropilfosfinska kiselina
Lesogaberan
SKF-97541: 3-Aminopropil(metil)fosfinska kiselina, više od 10 puta je potentniji od baklofena kao GABA_B agonist, ali je i GABA_C antagonist
CGP-44532

Pozitivni alosterni modulatori

Antagonisti

Saklofen
Faklofen
SCH-50911
CGP-35348
CGP-52432: 3-([(3,4-Dihlorofenil)metil]amino]propil) dietoksimetil)fosfinska kiselina, CAS# 139667-74-6
CGP-55845: (2S)-3-([(1S)-1-(3,4-Dihlorofenil)etil]amino-2-hidroksipropil)(fenilmetil)fosfinska kiselina, CAS# 149184-22-5
SGS-742^[12]^[13]

Reference

↑ Chen K, Li H, Ye N, Zhang J, Wang J (2005). „Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro”. Brain Res Bull 67 (4): 310–8. DOI:10.1016/j.brainresbull.2005.07.004. PMID 16182939.
↑ Dzitoyeva S, Dimitrijevic N, Manev H (2003). „Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence”. Proc Natl Acad Sci USA 100 (9): 5485–90. Bibcode 2003PNAS..100.5485D. DOI:10.1073/pnas.0830111100. PMC 154371. PMID 12692303.
↑ Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (2005). „Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)”. Eur J Pharmacol 519 (3): 246–52. DOI:10.1016/j.ejphar.2005.07.016. PMID 16129424.
↑ Manev H, Dimitrijevic N (2004). „Drosophila model for in vivo pharmacological analgesia research”. Eur J Pharmacol 491 (2-3): 207–8. DOI:10.1016/j.ejphar.2004.03.030. PMID 15140638.
↑ Dzitoyeva S, Gutnov A, Imbesi M, Dimitrijevic N, Manev H (2005). „Developmental role of GABAB(1) receptors in Drosophila”. Brain Res Dev Brain Res 158 (1-2): 111–4. DOI:10.1016/j.devbrainres.2005.06.005. PMID 16054235.
↑ ^6,0 ^6,1 MRC (Medical Research Council). 2003. Glutamate receptors: Structures and functions. Arhivirano 2007-09-15 na Wayback Machine-u University of Brisotol Centre for Synaptic Plasticity.
↑ Purves D., Augustine G.J., Fitzpatrick D., Katz L.C., LaMantia A.S., McNamara J.O., and Williams S.M. 2001. Neuroscience, Second Edition. Sinauer Associates, Inc.
↑ Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K (November 2001). „Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501”. Mol. Pharmacol. 60 (5): 963–71. PMID 11641424. Arhivirano iz originala na datum 2008-10-11. Pristupljeno 2014-04-26.
↑ Adams CL, Lawrence AJ (2007). „CGP7930: a positive allosteric modulator of the GABAB receptor”. CNS Drug Rev 13 (3): 308–16. DOI:10.1111/j.1527-3458.2007.00021.x. PMID 17894647.
↑ Paterson NE, Vlachou S, Guery S, Kaupmann K, Froestl W, Markou A (July 2008). „Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats”. J. Pharmacol. Exp. Ther. 326 (1): 306–14. DOI:10.1124/jpet.108.139204. PMC 2574924. PMID 18445779.
↑ Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K (October 2003). „N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function”. J. Pharmacol. Exp. Ther. 307 (1): 322–30. DOI:10.1124/jpet.103.053074. PMID 12954816.
↑ Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R (October 2004). „SGS742: the first GABA(B) receptor antagonist in clinical trials”. Biochemical Pharmacology 68 (8): 1479–87. DOI:10.1016/j.bcp.2004.07.030. PMID 15451390.
↑ Bullock R (January 2005). „SGS-742 Novartis”. Current Opinion in Investigational Drugs (London, England : 2000) 6 (1): 108–13. PMID 15675610.

Povezano

Vanjske veze

[Chen-1] Chen K, Li H, Ye N, Zhang J, Wang J (2005). „Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro”. Brain Res Bull 67 (4): 310–8. DOI:10.1016/j.brainresbull.2005.07.004. PMID 16182939.

[2] Dzitoyeva S, Dimitrijevic N, Manev H (2003). „Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence”. Proc Natl Acad Sci USA 100 (9): 5485–90. Bibcode 2003PNAS..100.5485D. DOI:10.1073/pnas.0830111100. PMC 154371. PMID 12692303.

[3] Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (2005). „Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)”. Eur J Pharmacol 519 (3): 246–52. DOI:10.1016/j.ejphar.2005.07.016. PMID 16129424.

[4] Manev H, Dimitrijevic N (2004). „Drosophila model for in vivo pharmacological analgesia research”. Eur J Pharmacol 491 (2-3): 207–8. DOI:10.1016/j.ejphar.2004.03.030. PMID 15140638.

[5] Dzitoyeva S, Gutnov A, Imbesi M, Dimitrijevic N, Manev H (2005). „Developmental role of GABAB(1) receptors in Drosophila”. Brain Res Dev Brain Res 158 (1-2): 111–4. DOI:10.1016/j.devbrainres.2005.06.005. PMID 16054235.

[MRC-6] 6,0 ^6,1 MRC (Medical Research Council). 2003. Glutamate receptors: Structures and functions. Arhivirano 2007-09-15 na Wayback Machine-u University of Brisotol Centre for Synaptic Plasticity.

[7] Purves D., Augustine G.J., Fitzpatrick D., Katz L.C., LaMantia A.S., McNamara J.O., and Williams S.M. 2001. Neuroscience, Second Edition. Sinauer Associates, Inc.

[pmid11641424-8] Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K (November 2001). „Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501”. Mol. Pharmacol. 60 (5): 963–71. PMID 11641424. Arhivirano iz originala na datum 2008-10-11. Pristupljeno 2014-04-26.

[pmid17894647-9] Adams CL, Lawrence AJ (2007). „CGP7930: a positive allosteric modulator of the GABAB receptor”. CNS Drug Rev 13 (3): 308–16. DOI:10.1111/j.1527-3458.2007.00021.x. PMID 17894647.

[pmid18445779-10] Paterson NE, Vlachou S, Guery S, Kaupmann K, Froestl W, Markou A (July 2008). „Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats”. J. Pharmacol. Exp. Ther. 326 (1): 306–14. DOI:10.1124/jpet.108.139204. PMC 2574924. PMID 18445779.

[pmid12954816-11] Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K (October 2003). „N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function”. J. Pharmacol. Exp. Ther. 307 (1): 322–30. DOI:10.1124/jpet.103.053074. PMID 12954816.

[pmid15451390-12] Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R (October 2004). „SGS742: the first GABA(B) receptor antagonist in clinical trials”. Biochemical Pharmacology 68 (8): 1479–87. DOI:10.1016/j.bcp.2004.07.030. PMID 15451390.

[pmid15675610-13] Bullock R (January 2005). „SGS-742 Novartis”. Current Opinion in Investigational Drugs (London, England : 2000) 6 (1): 108–13. PMID 15675610.

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