Skip to main content
placeholder image

Role of the ρ1 GABAC Receptor N‑Terminus in Assembly, Trafficking and Function

Journal Article


Abstract


  • The GABAC receptor and closely related GABAA receptor are

    members of the pentameric ligand-gated ion channels (pLGICs) superfamily

    and mediate inhibitory fast synaptic transmission in the nervous system. Each

    pLGIC subunit comprises an N-terminal extracellular agonist-binding domain

    followed by a channel domain and a variable intracellular domain. Available

    structural information shows that the core of the agonist-binding domain is a β

    sandwich of ten β-strands, which form the agonist-binding pocket at the subunit

    interface. This β-sandwich is preceded by an N-terminal α-helix in eukaryotic

    structures but not in prokaryotic structures. The N-terminal α-helix has been

    shown to be functionally essential in α7 nicotinic acetylcholine receptors.

    Sequence analysis of GABAC and GABAA receptors predicts an α-helix in a

    similar position but preceded by 8 to 46 additional residues, of unknown

    function, which we term the N-terminal extension. To test the functional role of

    both the N-terminal extension and the putative N-terminal α-helix in the ρ1

    GABAC receptor, we created a series of deletions from the N-terminus. The N-terminal extension was not functionally essential,

    but its removal did reduce both cell surface expression and cooperativity of agonist-gated channel function. Further deletion of

    the putative N-terminal α-helix abolished receptor function by preventing cell-surface expression. Our results further demonstrate

    the essential role of the N-terminal α-helix in the assembly and trafficking of eukaryotic pLGICs. They also provide evidence that

    the N-terminal extension, although not essential, contributes to receptor assembly, trafficking and conformational changes

    associated with ligand gating

UOW Authors


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

Publication Date


  • 2014

Citation


  • Wong, L., Tae, H. & Cromer, B. A. (2014). Role of the ρ1 GABAC Receptor N‑Terminus in Assembly, Trafficking and Function. ACS Chemical Neuroscience, 5 (12), 1266-1277.

Scopus Eid


  • 2-s2.0-84918539893

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 1266

End Page


  • 1277

Volume


  • 5

Issue


  • 12

Place Of Publication


  • United States

Abstract


  • The GABAC receptor and closely related GABAA receptor are

    members of the pentameric ligand-gated ion channels (pLGICs) superfamily

    and mediate inhibitory fast synaptic transmission in the nervous system. Each

    pLGIC subunit comprises an N-terminal extracellular agonist-binding domain

    followed by a channel domain and a variable intracellular domain. Available

    structural information shows that the core of the agonist-binding domain is a β

    sandwich of ten β-strands, which form the agonist-binding pocket at the subunit

    interface. This β-sandwich is preceded by an N-terminal α-helix in eukaryotic

    structures but not in prokaryotic structures. The N-terminal α-helix has been

    shown to be functionally essential in α7 nicotinic acetylcholine receptors.

    Sequence analysis of GABAC and GABAA receptors predicts an α-helix in a

    similar position but preceded by 8 to 46 additional residues, of unknown

    function, which we term the N-terminal extension. To test the functional role of

    both the N-terminal extension and the putative N-terminal α-helix in the ρ1

    GABAC receptor, we created a series of deletions from the N-terminus. The N-terminal extension was not functionally essential,

    but its removal did reduce both cell surface expression and cooperativity of agonist-gated channel function. Further deletion of

    the putative N-terminal α-helix abolished receptor function by preventing cell-surface expression. Our results further demonstrate

    the essential role of the N-terminal α-helix in the assembly and trafficking of eukaryotic pLGICs. They also provide evidence that

    the N-terminal extension, although not essential, contributes to receptor assembly, trafficking and conformational changes

    associated with ligand gating

UOW Authors


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

Publication Date


  • 2014

Citation


  • Wong, L., Tae, H. & Cromer, B. A. (2014). Role of the ρ1 GABAC Receptor N‑Terminus in Assembly, Trafficking and Function. ACS Chemical Neuroscience, 5 (12), 1266-1277.

Scopus Eid


  • 2-s2.0-84918539893

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 1266

End Page


  • 1277

Volume


  • 5

Issue


  • 12

Place Of Publication


  • United States