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January 2017

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Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure, Circulation, 2016; CIRCULATIONAHA.116.022852, DZHK authors: Nikolaev, Würtz, Voigt, Müller, Meder, Katus, Vettel, Lehmann, Backs, Lutz, Wieland

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Basic cardiovascular research deals with the molecular changes in heart muscle cells triggered, for example, by chronic activation of the sympathetic nervous system. So-called heterotrimeric GTP-binding proteins (G proteins) which pick up the signals of certain cell surface receptors, and amplify and transmit them into the cell in a targeted manner have an important role here. The research group of Professor Dr. Thomas Wieland at the Institute for Experimental and Clinical Pharmacology and Toxicology in Mannheim focuses on the enzyme nucleoside-diphosphate kinase (NDPK), whose task it is to provide the signal-transmitting G proteins with the nucleotide GTP required for their activation using the cellular energy supplier ATP.

By means of different animal models, cell-based analyses and experiments with purified proteins, the team was able to show that chronic activation of the sympathetic nervous system is responsible for the increased occurrence of NDPK-C. NDPK-C, in turn, specifically mediates the interaction of other NDPK isoforms with G proteins and allows increased movement of such complexes towards the receptors on the cell surface.

Interestingly, the known shift in the equilibrium between stimulatory and inhibitory G proteins, as occurs in the context of heart failure, also causes a shift in the interaction with NDPK-C. Whereas in healthy hearts, stimulatory G proteins are preferentially bound thus causing signal amplification, in failing hearts, more inhibitory G proteins are bound. This is probably one cause for the tonic attenuation of signals that induce contraction in diseased hearts. Blocking the binding of inhibitory G proteins with NDPK-C is therefore a potential new approach to the treatment of heart failure which the research group intends to pursue further.