Modulation of the Ca2+ conductance of nicotinic acetylcholine receptors by Lypd6

Darvas, Martin; Morsch, Marco; Racz, Ildiko; Ahmadi, Seifollah; Swandulla, Dieter; Zimmer, Andreas

doi:10.1016/j.euroneuro.2009.03.007

« Previous Next »European Neuropsychopharmacology
Volume 19, Issue 9 , Pages 670-681, September 2009

Modulation of the Ca²⁺ conductance of nicotinic acetylcholine receptors by Lypd6

Martin Darvas
- Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
- The first two authors contributed equally to this work.
Marco Morsch
- Institute of Physiology, University of Bonn, Bonn, Germany
- The first two authors contributed equally to this work.
Ildiko Racz
- Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
Seifollah Ahmadi
- Institute of Physiology, University of Bonn, Bonn, Germany
Dieter Swandulla
- Institute of Physiology, University of Bonn, Bonn, Germany
Andreas Zimmer
- Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
- Corresponding author. Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud Str. 25, D-53127 Bonn, Germany. Tel.: +49 228 688 5300; fax: +49 228 688 5301.

Received 4 December 2008; received in revised form 10 March 2009; accepted 31 March 2009. published online 30 April 2009.

Abstract

The agonist binding sensitivity and desensitization kinetics of nicotinic acetylcholine receptors (nAChRs) can be modulated by snake venom neurotoxins and related endogenous small proteins of the uPAR-Ly6 family. Here we identify Lypd6, a distantly related member of the u-PAR/Ly-6 family expressed in neurons as a novel modulator of nAChRs. Lypd6 overexpressed in trigeminal ganglia neurons selectively enhanced the Ca²⁺-component of nicotine-evoked currents through nAChRs, as evidenced by comparative whole-cell patch clamp recordings and Ca²⁺-imaging in wildtype and transgenic mice overexpressing Lypd6. In contrast, a knockdown of Lypd6 expression using siRNAs selectively reduced nicotine-evoked Ca²⁺-currents. Pharmacological experiments revealed that the nAChRs involved in this process are heteromers. Transgenic mice displayed behaviors that were indicative of an enhanced cholinergic tone, such as a higher locomotor arousal, increased prepulse-inhibition and hypoalgesia. These mice overexpressing Lypd6 mice were also more sensitive to the analgesic effects of nicotine. Transgenic mice expressing siRNAs directed against Lypd6 were unable to procreate, thus indicating a vital role for this protein. Taken together, Lypd6 seems to constitute a novel modulator of nAChRs that affects receptor function by selectively increasing Ca²⁺-influx through this ion channels.

Keywords: Transgenic mice, Allosteric modulator, Ion selectivity, Electrophysiology, Behavior, Receptor channel