Cardiac ion channels

The human heartbeat is controlled by a number of carefully orchestrated ion fluxes in and out of the cardiomyocyte. Its regulation is in part conducted by calmodulin, a small (148 amino acids) calcium binding protein. Calmodulin undergoes a large conformational change upon binding of calcium, and that alters its structure and ligand binding properties.

We are interested in the calcium-concentration dependent interactions between calmodulin and cardiac ion channels Cav1.2 and RyR2 (ryanodine receptor 2). How does this regulation work and what can go wrong? A number of mutations is known to disturb this regulation, both in the ion channels and – recently – also in calmodulin. The consequences are cardiac arrhythmia – even cardiac arrest. Also individuals without mutations can experience the same syndromes. We know, however, very little about the reasons and about how the dysregulation of ion channels happens.

Our goal is to investigate the mechanistic details of this interaction by NMR and other biophysical techniques.

Publications

• Wang K., Holt C., Lu J., Brohus M., Larsen K.T., Overgaard M.T., Wimmer R.* and van Petegem F.* (2018) Arrhythmia mutations in Calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel, PNAS, 115(45):E10556-E10565
• Søndergaard, M.T., Liu, Y., Larsen, K.T., Nani, A., Tian, X., Holt, C., Wang, R., Wimmer R., van Petegem F., Fill, M., Chen, S.r.W., Overgaard, M.T. (2017), The arrhythmogenic calmodulin p.Phe142Leu mutation impairs C-domain Ca2+-binding but not calmodulin-dependent inhibition of the cardiac ryanodine receptor, J.Biol.Chem, 292(4), p. 1383-1395

Natural compounds from fungi

Natural compounds are a large reservoir of new compounds with potentially new properties. Together with our colleagues from the Fungal Genomics group, we genetically manipulate fungi in order to overproduce secondary metabolites that we then characterize. We are interested in their structure, their biosynthetic pathway and their properties. Apart from fungal culturing and molecular biology (which is handled by our colleagues), we use LC-MS and NMR for this work

Publications

• Westphal KR, Werner MIH, Nielsen KAH, Sørensen JL, Andrushchenko V, Winde J, Hertz M, Jensen MA, Mortensen ML, Bour P, Sondergaard TE and Wimmer R. (2019), Characterization of eight novel spiroleptosphols from Fusarium avenaceum, Molecules, 24, 3498
• Westphal K.R., Nielsen K.A.H., Wollenberg R.D., Møllehøj M.B., Bachleitern S., Studt L., Lysøe E., Giese H., Wimmer R., Sørensen J.L. and Sondergaard T.E. (2019), Fusaoctaxin A, an example of a two-step mechanism for non-ribosomal peptide assembly and maturation in fungi, Toxins, 11(5). pii E277
• Westphal K.R., Wollenberg R.D., Herbst F.-A., Sørensen J.L., Sondergaard T.E. and Wimmer R. (2018), Enhancing the Production of the Fungal Pigment Aurofusarin in Fusarium graminearum, Toxins, 10 (11), 485
• Sørensen, J.L., Benfield, H.A., Wollenberg, R., Westphal, K., Wimmer R., Nielsen .M.R., Carere K.F., Covarelli L., Beccari, G., Powell J., Yamashino T., Kogler H., Søndergaard T.E., Gardiner D.M. (2017), The cereal pathogen Fusarium pseudograminearum produces a new class of active cytokinins during infection, Mol.Plant.Pathology, 19(5), p. 1140-1154

Medical metabolomics

Metabolomics is the study of the body of small molecules (metabolites) present in a biological system. The metabolome of human body fluids can give valuable hints about the state of the body, whether it is diseased, recovering, … Together with Aalborg University hospital we are looking at samples from patients suffering from different diseases to help understand the biochemical processes happening around the disease progression or recovery.  

Publications

• Hanifa M.A., Skott M., Maltesen R.G., Rasmussen B.S., Nielsen S., Frøkiær J., Ring T and Wimmer R. (2019) Tissue, urine and blood metabolite signatures of chronic kidney disease in the 5/6 nephrectomy rat model, Metabolomics, 15(8):112
• Maltesen R.G., Buggeskov K.B., Andersen C.B., Plovsing R., Wimmer R. and Rasmussen, B.S. (2018), Lung protection during cardiopulmonary bypass in cardiac surgery - from a molecular and histological perspective, Metabolites, 8(4), pii: E54
• Maltesen R.G., Hanifa M.A., Pedersen S., Kucheryavskiy S.V., Kristensen S.R., Rasmussen B.S. and Wimmer R. (2017), Metabotyping Patients' Journeys Reveals Early Predisposition to Lung Injury after Cardiac Surgery, Sci.Rep. 7:40275

Equipment

• NMR: Bruker 600 MHz, cryogenic probe
• LC-MS: ESI-qTOF
• Waters autopurificator: preparative HPLC with MS-detection and MS-guided fractionation
• CD, Fluorescence, ITC, MALDI-TOF MS