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Assembly, trafficking and function of α1β2γ2 GABAA receptors are regulated by N‐terminal regions, in a subunit‐specific manner

Journal Article


Abstract


  • GABAAreceptors are pentameric ligand-gated ion channelsthat mediate inhibitory fast synaptic transmission in the centralnervous system. Consistent with recent pentameric ligand-gated ion channels structures, sequence analysis predicts ana-helix near the N-terminus of each GABAAreceptor subunit.Preceding each a-helix are 8–36 additional residues, which weterm the N-terminal extension. In homomeric GABACrecep-tors and nicotinic acetylcholine receptors, the N-terminal a-helix is functionally essential. Here, we determined the role ofthe N-terminal extension and putative a-helix in heteromerica1b2c2 GABAAreceptors. This role was most prominent in thea1 subunit, with deletion of the N-terminal extension or furtherdeletion of the putative a-helix both dramatically reduced thenumber of functional receptors at the cell surface. Conversely,deletion of the b2orc2 N-terminal extension had little effect onthe number of functional cell surface receptors. Additionaldeletion of the putative a-helix in the b2orc2 subunits did,however, decrease both functional cell surface receptors andincorporation of the c2 subunit into mature receptors. In the b 2subunit only, a-helix deletions affected GABA sensitivity anddesensitization. Our findings demonstrate that N-terminalextensions and a-helices make key subunit-specific contribu-tions to assembly, consistent with both regions being involvedin inter-subunit interactions.

UOW Authors


  •   Wong, Lik Wei (external author)
  •   Tae, Han Shen
  •   Cromer, Brett A. (external author)

Publication Date


  • 2015

Citation


  • Wong, L., Tae, H. & Cromer, B. A. (2015). Assembly, trafficking and function of α1β2γ2 GABAA receptors are regulated by N‐terminal regions, in a subunit‐specific manner. Journal of Neurochemistry, 134 (5), 819-832.

Scopus Eid


  • 2-s2.0-84938970306

Has Global Citation Frequency


Number Of Pages


  • 13

Start Page


  • 819

End Page


  • 832

Volume


  • 134

Issue


  • 5

Place Of Publication


  • United Kingdom

Abstract


  • GABAAreceptors are pentameric ligand-gated ion channelsthat mediate inhibitory fast synaptic transmission in the centralnervous system. Consistent with recent pentameric ligand-gated ion channels structures, sequence analysis predicts ana-helix near the N-terminus of each GABAAreceptor subunit.Preceding each a-helix are 8–36 additional residues, which weterm the N-terminal extension. In homomeric GABACrecep-tors and nicotinic acetylcholine receptors, the N-terminal a-helix is functionally essential. Here, we determined the role ofthe N-terminal extension and putative a-helix in heteromerica1b2c2 GABAAreceptors. This role was most prominent in thea1 subunit, with deletion of the N-terminal extension or furtherdeletion of the putative a-helix both dramatically reduced thenumber of functional receptors at the cell surface. Conversely,deletion of the b2orc2 N-terminal extension had little effect onthe number of functional cell surface receptors. Additionaldeletion of the putative a-helix in the b2orc2 subunits did,however, decrease both functional cell surface receptors andincorporation of the c2 subunit into mature receptors. In the b 2subunit only, a-helix deletions affected GABA sensitivity anddesensitization. Our findings demonstrate that N-terminalextensions and a-helices make key subunit-specific contribu-tions to assembly, consistent with both regions being involvedin inter-subunit interactions.

UOW Authors


  •   Wong, Lik Wei (external author)
  •   Tae, Han Shen
  •   Cromer, Brett A. (external author)

Publication Date


  • 2015

Citation


  • Wong, L., Tae, H. & Cromer, B. A. (2015). Assembly, trafficking and function of α1β2γ2 GABAA receptors are regulated by N‐terminal regions, in a subunit‐specific manner. Journal of Neurochemistry, 134 (5), 819-832.

Scopus Eid


  • 2-s2.0-84938970306

Has Global Citation Frequency


Number Of Pages


  • 13

Start Page


  • 819

End Page


  • 832

Volume


  • 134

Issue


  • 5

Place Of Publication


  • United Kingdom