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HEVEKER , Nikolaus  PhD
 
 
     
 
Research Axis
 
   
 
 
 
Research Theme
 
   
 
 
 
Address
 
 
CHU Sainte-Justine
 
 
Centre de recherche
 
 
3175 Chemin de la Côte Sainte-Catherine
 
 
Montréal  (QC), Canada
 
 
H3T 1C5
 
     
 
Phone
 
 
514 345-4931 #4190
 
 
 
 
Fax
 
 
514 345-4801
 
     
     
     

nikolaus.heveker@recherche-ste-justine.qc.ca
 
 
Career Summary, Research Topics and Interests
 

Title

  • Research Associate Professor, Department of Biochemistry, University of Montreal.

Education

  • Postdoctoral Fellow, Institut Cochin, Paris, 1996-2001.

  • Postdoctoral Fellow, Institut Pasteur, Paris, 1993-1996.

  • PhD in Biochemistry, Humboldt Universität, Berlin, 1993.

Research Interests

Seven transmembrane domain receptors (7TMRs) control the function of the endocrine, nervous and immune systems. Ligand binding to 7TMRs activates diverse downstream effectors, the most prominent being the heterotrimeric G proteins. How 7TMR diversity in signalling, which is highly relevant for disease genesis and treatment, is achieved and regulated remains to be elucidated. At present, 7TMR inhibitors are the largest group of prescription drugs. A better knowledge of the mechanisms of 7TMR response diversity might permit to selectively interfere with receptor functions, rather than with ligand binding, and thus to combine higher drug efficiency with lower side effects.

Chemokine receptors are dimeric 7TMR that bind chemokines, which are small secreted proteins (6-8 kD). The chemokine signalling hallmark is chemotaxis by motile cells up a chemokine concentration gradient. However, multiple other effects have come to light and some chemokine receptors do not induce chemotaxis at all. Chemokine signalling is paramount for immune system development and function, and aberrant chemokine signalling is involved in immune deficiencies, autoimmunity and inflammatory diseases. For example, CCR2 plays a role in the atherosclerotic plaque formation. In addition, chemokine receptors such as CXCR4 and CXCR7 play a paramount role in cancer progression and metastasis and stem cell homing to bone marrow niches. Finally, CCR5 and CXCR4 serve as entry receptors for the human immunodeficiency virus HIV-1 into target cells, acting with the 1TMR CD4.

The conceptual framework of 7TMR activation is still evolving, but is critical for selective therapeutic intervention with specific 7TMR functions. The traditional theoretical models of 7TMR activation were subsequently difficult to reconcile with data accumulating over decades. Thus, new concepts are forwarded that could lead to a radically renewed understanding of 7TMR signalling diversity. One of these concepts is functional selectivity. According to this concept, different receptor ligands stabilize different receptor conformations, thereby activating distinct signalling pathways. No single active or inactive receptor conformation is defined, but a number of receptor conformations coexist. As most data supporting functional selectivity derive from studies with synthetic rather than natural ligands, its pertinence for physiological processes still remains to be proven.

Our research investigates chemokine receptor structure-function relationships under the aspect of functional selectivity. We analyze the conformational and functional effects of different natural CCR2 ligands. CXCR7 functions are investigated. In addition, we study receptor oligomerization, with other 7TMRs or other additional proteins, and its impact on chemokine receptor function. The methods used are related to molecular biology, signalling techniques, HIV infection and the biophysical BRET technique (Bioluminescence Resonance Energy Transfer), for which our laboratory has developed expertise.

 
Awards and Distinctions
 
  • New Investigator Award, Canadian Institutes of Health Research, 2007-2012.

  • Junior 2 Research Scholar, Fonds de la recherche en santé du Québec, 2003-2005.

 
Most Important Publications Selected by the Researcher
 
Berchiche Y, Gravel S, Pelletier M-E, St-Onge G, Heveker N,
Different effects of the different natural CC-chemokine receptor 2B (CCR2B) ligands on {beta}-arrestin recruitment, G{alpha}i signalling, and receptor internalization
Mol Pharmacol 2011  488-498.
 
   
Gravel S, Malouf C, Boulais PE, Berchiche Y, Oishi S, Fujii N, Leduc R, Sinnett D, Heveker N,
The peptidomimetic CXCR4 antagonist TC14012 recruits {beta}-arrestin to CXCR7 roles of receptor domains
J Biol Chem 2010  37939-37943.
 
   
Kalatskaya I, Berchiche Y, Gravel S, Limberg B, Rosenbaum J, Heveker N,
AMD3100 is a CXCR7 ligand with allosteric agonist properties
Mol Pharmacol 2009  1240-1247.
 
   
Berchiche Y, Chow KY, Lagane B, Leduc M, Percherancier Y, Fujii N, Tamamura H, Bachelerie F, Heveker N,
Direct assessment of CXCR4 mutant conformations reveals complex link between receptor structure and Gai activation
J Biol Chem 2007  5111-5115.
 
   
Percherancier Y, Berchiche Y, Slight I, Volkmer-Engert R, Tamamura H, Fujii N, Bouvier M, Heveker N,
Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers
J Biol Chem 2005  9895-9903.
 
   
Publications reported to FRSQ
 
 
 
 
























 
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