GABA receptor

From Ganfyd

GABA-A receptors are ligand-gated chloride channels composed of 5 variable subunits and there are at least 6 alpha, 3 beta, 3 gamma, 1 delta, and 2 rho isoforms. The majority of these receptors are coded by the GABRA1, GABRB2 and GABRG2 genes. Zinc ions usually modulate their function except with complexes containing the GABRB2 subunit.

• α1 isoform GABRA1 of the alpha subunit is coded at 5q34-q35
  • Mutations are associated with types of juvenile myoclonic epilepsy and absence epilepsy
• α2 isoform GABRA2 of the alpha subunit is coded at 4p13-p12
  • Mutations are associated with susceptibility to alcoholism
• α3 isoform GABRA3 of the alpha subunit is coded at Xq28
• α4 isoform GABRA4 of the alpha subunit is coded at 4p14-q12
  • Mutations interact with GABRB1 to change risk autism
• α5 isoform GABRA5 of the alpha subunit is coded at 15q11.2-q12
  • Mutations associated with bipolar affective disorder
• α6 isoform GABRA6 of the alpha subunit is coded at 5q31.1-q35
  • Postulated to be important in cerebellar motor control
• β1 isoform GABRB1 of the beta subunit is coded at 4p13-p12
• β2 isoform GABRB2 of the beta subunit is coded at 5q34-q35
• β2 isoform GABRB3 of the beta subunit is coded for at 15q11.2-q12
  • Deletions of this region result in Angelman syndrome and Prader-Willi syndrome some of whose features may reflect deficiency of this subunit
• δ isoform GABRD is the delta subunit coded for at 1p36.3
  • Mutations seem to result in generalized epilepsy with febrile seizures
  • Three transcripts
    • GABRD1a
    • GABRD1b
    • GABRD1c
• γ1 isoform GABRG1 of the gamma subunit is coded at 4p14-q21.1
• γ2 isoform GABRG2 of the gamma subunit is coded at 5q31.1-q33.1
  • Allows GABA-A receptors yo complex selectively with the dopamine D5 receptor
  • Has benzodiazepine binding site
  • Mutations associated with types of generalized epilepsy with febrile seizures
• γ3 isoform GABRG3 of the gamma subunit is coded at 15q11.2-q12
• ρ1 -rho1- GABRR1 subunit coded for at 6q14-q21
• ρ2 -rho2- GABRR2 subunit also coded for at 6q14-q21

Also other isoforms with less well characterised function are:

• GABRE is a transcript from Xq28
  • Coding region associated with early onset Parkinsonism and mental retardation
• GABRQ is a transcript from Xq28 with beta subunit homology.
• GABRP is a transcript from 5q32-q33 which is mainly active in the uterus and alters the sensitivity of recombinant receptors to steroid modulators like pregnanolone

Other proteins associated with the GABA-A receptor include:

• A kinesin binding GABA-A receptor interacting factor ALS2CR3 is coded for at 2q33-q34 and is mutated in juvenile amyotrophic lateral sclerosis-2.
• Ubiquitin-like proteins:
  • GABARAPL1 coded for at 12p12.3
  • GABARAPL2 coded for at 16q22.3-q24.1

Benzodiazepine binding to GABA-A is at a specific site (BzR), close to the alpha/gamma subunit interface. The alpha subunit is the main determinant of benzodiazepine ligand selectivity with α1 associated with the sedative action, α2 or α3 subtypes may mediate anxiolytic activity and α5 subtype with cognitive actions^[1].

GABA-B receptors have two subunits:

• R1 subunit GABBR1 coded for at 6p21.3 has at least 3 transcripts:
  • GABBR1a
  • GABBR1b
  • GABBR1c
• R2 subunit GABBR2 is coded for by the GPR51 gene at 9q22.
  • Nicotine dependence function of mutations
  • Dimers of GABBR1a/b and GABBR2 are necessary for activation of Kir3-type potassium channels efficiently

References