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Positive Modulation of the Glycine Receptor by Means of Glycine Receptor-Binding Aptamers
KTH, School of Biotechnology (BIO), Protein Technology.
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2015 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 20, no 9, 1112-1123 p.Article in journal (Refereed) Published
Abstract [en]

According to the gate control theory of pain, the glycine receptors (GlyRs) are putative targets for development of therapeutic analgesics. A possible approach for novel analgesics is to develop a positive modulator of the glycine-activated Cl- channels. Unfortunately, there has been limited success in developing drug-like small molecules to study the impact of agonists or positive modulators on GlyRs. Eight RNA aptamers with low nanomolar affinity to GlyR1 were generated, and their pharmacological properties analyzed. Cytochemistry using fluorescein-labeled aptamers demonstrated GlyR1-dependent binding to the plasma membrane but also intracellular binding. Using a fluorescent membrane potential assay, we could identify five aptamers to be positive modulators. The positive modulation of one of the aptamers was confirmed by patch-clamp electrophysiology on L(tk) cells expressing GlyR1 and/or GlyR1. This aptamer potentiated whole-cell Cl- currents in the presence of low concentrations of glycine. To our knowledge, this is the first demonstration ever of RNA aptamers acting as positive modulators for an ion channel. We believe that these aptamers are unique and valuable tools for further studies of GlyR biology and possibly also as tools for assay development in identifying small-molecule agonists and positive modulators.

Place, publisher, year, edition, pages
Sage Publications, 2015. Vol. 20, no 9, 1112-1123 p.
Keyword [en]
glycine receptor, aptamer, surface plasmon resonance, fluorescent membrane potential, patch-clamp electrophysiology
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:kth:diva-174916DOI: 10.1177/1087057115590575ISI: 000361605800006PubMedID: 26071243Scopus ID: 2-s2.0-84942099427OAI: oai:DiVA.org:kth-174916DiVA: diva2:865428
Funder
AstraZenecaVINNOVA
Note

QC 20151028

Available from: 2015-10-28 Created: 2015-10-09 Last updated: 2017-12-01Bibliographically approved

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