Abstract:
:Glycine receptor (GlyR) truncations in the intracellular TM3-4 loop, documented in patients suffering from hyperekplexia and in the mouse mutant oscillator, lead to non-functionality of GlyRs. The missing part that contains the TM3-4 loop, TM4 and C-terminal sequences is essential for pentameric receptor arrangements. In vitro co-expressions of GlyRα1-truncated N-domains and C-domains were able to restore ion channel function. An ionic interaction between both domains was hypothesized as the underlying mechanism. Here, we analysed the proposed ionic interaction between GlyR N- and C-domains using C-terminal constructs with either positively or negatively charged N-termini. Charged residues at the N-terminus of the C-domain did interfere with receptor surface expression and ion channel function. In particular, presence of negatively charged residues at the N-terminus led to significantly decreased ion channel function. Presence of positive charges resulted in reduced maximal currents possibly as a result of repulsion of both domains. If the C-domain was tagged by a myc-epitope, low maximal current amplitudes were detected. Intrinsic charges of the myc-epitope and charged N-terminal ends of the C-domain most probably induce intramolecular interactions. These interactions might hinder the close proximity of C-domains and N-domains, which is a prerequisite for functional ion channel configurations. The remaining basic subdomains close to TM3 and 4 were sufficient for domain complementation and functional ion channel formation. Thus, these basic subdomains forming α-helical elements or an intracellular portal represent attractants for incoming negatively charged chloride ions and interact with the phospholipids thereby stabilizing the GlyR in a conformation that allows ion channel opening.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Langlhofer G,Villmann Cdoi
10.1111/jnc.14049subject
Has Abstractpub_date
2017-07-01 00:00:00pages
41-55issue
1eissn
0022-3042issn
1471-4159journal_volume
142pub_type
杂志文章abstract::Over the last two decades, a number of studies have underlined the importance of lysosomal-based degradative pathways in maintaining the homeostasis of post-mitotic cells, and revealed the remarkable contribution of a functional autophagic machinery in the promotion of longevity. In contrast, defects in the clearance ...
journal_title:Journal of neurochemistry
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doi:10.1046/j.1471-4159.1994.62020788.x
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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