Neprilysin 4 regulates muscle contraction by modulating SERCA activity

RONJA SCHIEMANN; MIRKO HUSKEN; MICHAEL STUKE; PAOLA FERRERO; HEIKO HARTEN

Cologne

Congreso; German Drosophila Meeting 2016; 2016

German Drosophila Meeting 2016Neprilysin 4 regulates muscle contraction by modulating SERCA activityRonja Schiemann, Mirko Hüsken, Michael Stuke, Paola Ferrero, Heiko HartenThe ability of muscle fibers to contract is based on well characterized molecular processes, with thecytosolic calcium concentration representing a crucial parameter. A major player responsible forregulating this concentration is the sarcoplasmic/endoplasmic reticulum calcium ATPase, SERCA, thatactively transports calcium from the cytosol of the muscle cells into a specialized storage organelle,the sarcoplasmic reticulum, thereby reducing cytosolic calcium levels and marking the beginning ofthe muscle relaxation phase. Based on this essential functionality, tight regulation of SERCA-activity isvital to the proper functionality of muscle tissue.As recently shown in Drosophila melanogaster, activity of SERCA is regulated by certain peptides thatbind to the enzyme and thereby significantly reduce its activity. Loss-of-Function mutants for thesepeptides exhibit significantly impaired calcium transport in heart cells, concomitant with severe heartarrhythmicity. Interestingly, we could show that increased abundance of the peptidase Neprilysin 4(Nep4) also causes heart arrhythmicity. Furthermore, SERCA-activity is considerably elevated incorresponding animals, compared to wildtype. In addition, we found clear colocalization betweenSERCA and Nep4 in muscle cells, which also represents good evidence for a functional relationbetween these two enzymes.In future experiments we aim to confirm the hypothesis that Nep4 is able to cleave and therebyinactivate the SERCA-regulative peptides. This functionality would identify the neprilysin as a noveland essential factor regulating SERCA-activity. Confirming our hypothesis would not only significantlyadvance the current understanding of muscle physiology and functionality but could represent thebasis for the development of innovative therapies against predominant heart and muscle diseases.