A National Research Priority Program of  
the

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Funding Period 2011 - 2013

P9

Structure-function relationships of the VILIP-1 -alpha4beta2 nAChR interaction – implications for nicotine-induced functional up-regulation of the alpha4beta2 nicotinic acetylcholine receptor (BR1579/9-2 and MA1842/8-2)

 

Prof. Dr. Karl-Heinz Braunewell (Principle Investigator)

Ruhr-Universität Bochum

Department of Experimental Neurophysiology

MA 04/48

44780 Bochum

+49-234-32-25226

Fax: +49-234-32-14490

Braunewell(at)neurop.rub.de

 

Together with:

 

Prof. Dr. Denise Manahan-Vaughan

Department of Experimental Neurophysiology

Medical Faculty, Ruhr University Bochum

Universitätsstrasse 150

MABF 01/116

44780 Bochum

+49-234-32 22042

Denise.manahan-vaughan(at)rub.de

 

The precise molecular mechanisms of functional upregulation of alpha4beta2 nicotinic acetylcholine receptors (nAChR) are not yet known. Our recent results support the hypothesis that nicotine activates the Ca2+-myristoyl switch of the neuronal Ca2+-sensor protein VILIP-1 (Zhao et al., 2008a), and that VILIP-1 represents a novel functional modulator of alpha4beta2 nAChRs affecting receptor trafficking and functional upregulation in hippocampal neurons (Zhao & Braunewell, 2008, Zhao et al., 2008b). This may comprise a novel physiological mechanism underlying the positive nicotine effects on cognition and memory. Moreover, pathological glutamatergic regulation of VILIP-1 expression, in conjunction with its interaction partner alpha4beta2 nAChR, leads to changes in GABAergic activity in the hippocampal network and, thus, might be involved in cognitive impairments in schizophrenia (Zhao et al., 2008a, Gierke et al., 2008). In the second funding period, we will investigate structure-function relationship of the VILIP-1-nAChR complex. We will study the molecular determinants of the interaction of VILIP-1 with the alpha4beta2nAChR, with phospholipids and dimer formation in bimolecular fluorescence complementation (BiFC) and Co-IP assays. We will designs mutants which show deficits in interactions and analyze their impact on the VILIP-1 effect on alpha4beta2 receptor trafficking by using confocal microscopy, and on the functional upregulation of alpha4beta2 nAChRs in electrophysiological patch-clamp experiments. Moreover, we will test the significance of the VILIP-1-nAChR complex for synaptic plasticity and learning behaviour in health and in a schizophrenia disease model.