Neprilysin 4 regulates muscle contraction by modulating SERCA activity

PAOLA FERRERO; ACHIM PAULULAT; HEIKO HARTEN; RONJA SCHIEMANN; MICHAEL STUKE

Londres

Congreso; 25th European Drosophila Research Conference 2017; 2017

Neprilysin 4 regulates muscle contraction by modulating SERCA activityRonja Schiemann, Michael Stuke , Paola Ferrero, Achim Paululat, 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,which actively transports calcium from the cytosol of muscle cells into the sarcoplasmic reticulum,thereby reducing cytosolic calcium levels and marking the beginning of the muscle relaxation phase.Based on this essential functionality, tight regulation of SERCA-activity is vital to the properfunctionality of muscle tissue.As recently shown in Drosophila melanogaster, activity of SERCA is regulated by certain peptides thatbind SERCA and thereby significantly reduce its activity. Loss-of-Function mutants for these peptidesexhibit impaired calcium transport in heart cells, concomitant with severe heart arrhythmia.Interestingly, we could show that increased abundance of the peptidase Neprilysin 4 (Nep4) alsocauses heart arrhythmia and SERCA-activity is considerably elevated in corresponding animals,compared to wildtype. In addition, the clear colocalization between SERCA and Nep4 in muscle cellsalso indicates a functional relation between these two enzymes.In current experiments we test whether Nep4 is able to cleave and thereby inactivate the SERCA-regulative peptides. This functionality would identify the neprilysin as a novel and essential factorregulating SERCA-activity. By confirming the orientation of Nep4 in the SR membrane we alreadyachieved first insight into the possible underlying cleavage mechanism. Confirming our hypothesiswould not only significantly advance the current understanding of muscle physiology andfunctionality, but could represent the basis for the development of innovative therapies againstpredominant heart and muscle diseases.