Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 8, Pages 2440-2452Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4400-08.2009
Keywords
chloride channel; domain; glycine receptor; TM3-TM4 loop; rescue; inhibition
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Funding
- Deutsche Forschungsgemeinschaft Grants [BE1138/5-6, STA399/9-1, SFB636/A4]
- European Union [HEALTH-F4-2008-202088]
- Johannes und Frieda Marohn-Stiftung
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The oscillator mouse (Glra1(spd-ot)) carries a 9bp microdeletion plus a 2bp microinsertion in the glycine receptor alpha 1 subunit gene, resulting in the absence of functional alpha 1 polypeptides from the CNS and lethality 3 weeks after birth. Depending on differential use of two splice acceptor sites in exon 9 of the Glra1 gene, the mutant allele encodes either a truncated alpha 1 subunit (spd(ot)-trc) or a polypeptide with a C-terminal missense sequence (spd(ot)-elg). During recombinant expression, both splice variants fail to form ion channels. In complementation studies, a tail construct, encoding the deleted C-terminal sequence, was coexpressed with both mutants. Coexpression with spd(ot)-trc produced glycine-gated ion channels. Rescue efficiency was increased by inclusion of the wild-type motif RRKRRH. In cultured spinal cord neurons from oscillator homozygotes, viral infection with recombinant C-terminal tail constructs resulted in appearance of endogenous alpha 1 antigen. The functional rescue of alpha 1 mutants by the C-terminal tail polypeptides argues for a modular subunit architecture of members of the Cys-loop receptor family.
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