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Four novel interaction partners demonstrate diverse modulatory effects on voltage-gated CaV2.2 Ca2+ channels

  • Robert Mallmann
  • Katarina Ondacova
  • Lucia Moravcikova
  • Bohumila Jurkovicova-Tarabova
  • Michaela Pavlovicova
  • Lucia Lichvarova
  • Viera Kominkova
  • Norbert Klugbauer
  • Lubica LacinovaEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters

Abstract

Voltage-gated Ca2+ channels are embedded in a network of protein interactions that are fundamental for channel function and modulation. Different strategies such as high-resolution quantitative MS analyses and yeast-two hybrid screens have been used to uncover these Ca2+ channel nanodomains. We applied the yeast split-ubiquitin system with its specific advantages to search for interaction partners of the CaV2.2 Ca2+ channel and identified four proteins: reticulon 1 (RTN1), member 1 of solute carrier family 38 (SLC38), prostaglandin D2 synthase (PTGDS) and transmembrane protein 223 (TMEM223). Interactions were verified using the yeast split-ubiquitin system and narrowed down to CaV2.2 domain IV. Colocalization studies using fluorescent constructs demonstrated defined regions of subcellular localization. Detailed electrophysiological studies revealed that coexpression of RTN1 modulated CaV2.2 channels only to a minor extent. SLC38 accelerated the cumulative current inactivation during a high-frequency train of brief depolarizing pulses. As neurons expressing CaV2.2 channels were exposed to high-frequency bursts under physiological conditions, observed regulation may have a negative modulatory effect on transmitter release. Coexpression of PTGDS significantly lowered the average current density and slowed the kinetics of cumulative current inactivation. Since the latter effect was not significant, it may only partly compensate the first one under physiological conditions. Expression of TMEM223 lowered the average current density, accelerated the kinetics of cumulative current inactivation and slowed the kinetics of recovery from inactivation. Therefore, TMEM223 and, to a lesser extent, PTGDS, may negatively modulate Ca2+ entry required for transmitter release and/or for dendritic plasticity under physiological conditions.

Keywords

CaV2.2 channel Yeast split-ubiquitin system Reticulon 1 Solute carrier family 38 member 1 Prostaglandin D2 synthase Transmembrane protein 223 

Notes

Acknowledgments

We thank U. Christoph and E. Kocurova for technical assistance. This work was supported by grant VEGA 2/0107/16 to LLa and by grant from DAAD/SAS to LLa and NK.

Author contribution

LM, KO, BJT, MP and LLi acquired, analysed and interpreted electrophysiology data. VK analysed and interpreted electrophysiology data. RM performed YTH screening experiments and colocalization studies and wrote the paper. NK and LLa provided critical experimental expertise and technology, designed experiments and wrote the paper.

Compliance with ethical standards

Competing interests

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Robert Mallmann
    • 1
  • Katarina Ondacova
    • 2
  • Lucia Moravcikova
    • 2
  • Bohumila Jurkovicova-Tarabova
    • 2
  • Michaela Pavlovicova
    • 2
  • Lucia Lichvarova
    • 2
  • Viera Kominkova
    • 2
  • Norbert Klugbauer
    • 1
  • Lubica Lacinova
    • 2
    Email author return OK on get
  1. 1.Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Fakultät für MedizinAlbert-Ludwigs-Universität FreiburgFreiburgGermany
  2. 2.Center of BioscienceInstitute for Molecular Physiology and GeneticsBratislavaSlovakia

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