Loland Lab – University of Copenhagen

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CNS > Research > Section for Molecular and Cellular Neuroscience > Loland Lab

Loland Lab

The Loland lab focuses on structure-function relationships in membrane transporters with focus on the Neurotransmitter:Sodium Symporter (NSS) class of proteins.

We elucidate at atomic level resolution the molecular mechanisms within the proteins that mediate substrate transport. The focus is on identification of specific domainsthat h undergoes conformational changes during substrate binding and translocation. We also map binding sites and binding modes for substrates (e.g. dopamine, serotonin, amphetamine) and inhibitory drugs (e.g. cocaine, antidepressants).

The methods we use to address these issues include advanced biophysics on purified proteins and all aspects of biochemistry and molecular pharmacology on cell systems.

Recent specific examples of our work include:

1) Use of transition metal ion FRET to directly assess conformational changes in NSS proteins. With this method, we made the intriguing finding that potassium plays a hitherto unrecognized central role in the translocation process of NSS proteins.

2) X-ray crystallography and advanced fluorescent-based approaches have identified a novel conformational state in NSS proteins, which represents an unrecognized rate-limiting barrier in the transport mechanism.

3) We have used hydrogen-deuterium exchange mass spectrometry (HDx-MS) to provide detailed information on the global conformational transitions within the entire protein during transport. This revealed that transient unwinding of multiple helical domains plays a role in substrate translocation.

4) Using classical molecular pharmacological assays, we have established that modafinil analogues through their interaction with the dopamine transporter can serve as lead compounds for the development of the first medical treatment for cocaine abuse.

5) In the serotonin transporter, our investigation on substrate and inhibitor binding sites has recently led to the identification of novel high-affinity allosteric inhibitors of the protein.

6) We have assessed substrate binding with solid state NMR. The results settle a long-standing dispute in the field providing evidence for a single substrate-binding site. This goes against current biochemical and pharmacological findings, which suggest two sites.

Key publications last 10 years

  • C S. Erlendsson, K. Gotfryd… U. Gether, K. Teilum, C.J. Loland :Direct Assessment of Substrate Binding to the Neurotransmitter:Sodium Symporter LeuT by Solid State NMR. eLife (2017), 6, e19314 (Impact Factor: 8.30)

  • C.B. Billesbølle, J.S. Mortensen….H.H. Sitte, U. Gether, C.J. Loland :Transition metal ion FRET uncovers K+ regulation of a neurotransmitter:sodium symporter. Nature Communications (2016) 7, 12755 (Impact Factor: 11.3)
  • M.A.B. Larsen, P. Plenge ….K. Strømgaard, B. Bang-Andersen, C.J. Loland :Structure-activity relationship studies of citalopram derivatives: Examining substituents conferring selectivity for the allosteric site in the serotonin transporter. Br J Pharmacol (2016) 173, 925-36 (Impact Factor: 5.26)
  • M. Ehsan, Y. Du….C.J. Loland, G. Skiniotis, L. Guan, B. Byrne, B.K. Kobilka, P.S. Chae. Highly Branched Pentasaccharide-Bearing Amphiphiles for Membrane Protein Studies. JACS (2016), 138, 3789-96 (Impact Factor: 13.0)
  • C.J. Loland, M. Mereu…J. L. Katz, G. Tanda,  A. H. Newman: R-Modafinil (Armodafinil): A unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry (2012), 72, 405-13 (Impact Factor: 9.25)
  • P.S. Chae, S.G. Rasmussen…C.J. Loland…B. Byrne, B. Kobilka, S.H. Gellman: Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nature Methods (2010) 7, 1003-8 (IF: 20.7)
  • T. Beuming, J. Kniazeff, M. … H. Weinstein, U. Gether, and C. J. Loland:  The Binding Sites for Cocaine and Dopamine in the Dopamine Transporter are Overlapping. Nature Neuroscience (2008) 11, 780-789 ( Impact Factor: 14.2)

Overall publication metrics: Number of peer reviewed papers: 59; H-index: 23