A novel role for the non‐catalytic intracellular domain of Neprilysins in muscle physiology

Panz, Mareike; Vitos-Faleato, Jessica; Jendretzki, Arne; Heinisch, Jürgen J.; Paululat, Achim; Meyer, Heiko

doi:10.1111/boc.201100069

Cited by 9 publications

(16 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These distinct effects demonstrate that lethality during early development is caused exclusively by a detrimental increase in catalytic activity, whereas late larval lethality appears to be a consequence of multiple physiological impairments. Comparable overexpression levels of the wild-type enzyme and the mutated construct were demonstrated previously (Panz et al, 2012). Muscle-specific knockdown of nep4 slightly increased embryonic mortality, but the majority of the respective animals died during metamorphosis (Figure 1A).…”

Section: Resultssupporting

confidence: 73%

“…As depicted in Figure 4, in body wall muscles Nep4 exhibits a dual localization: in addition to localizing to membranes continuous with the nuclear membrane (Figure 4A, arrowheads), which we previously identified as related to the sarco/endoplasmic reticulum (Panz et al, 2012), the peptidase accumulates at the surface of the muscles (Figure 4A, arrows). The latter localization is consistent with ectoenzymatic activity and indicative of a function in regulating the homeostasis of hemolymph circulating peptides.…”

Section: Resultsmentioning

confidence: 81%

“…In previous experiments, we showed that Nep4 is expressed in larval body wall muscles and that increased expression of the peptidase in this tissue interferes with muscle function and integrity and severely impairs movement of the larvae (Panz et al, 2012). In the present study, we found that an increase in Nep4A in muscle cells ( mef2 -Gal4 driver) also induced biphasic lethality.…”

Section: Resultsmentioning

confidence: 99%

“…With respect to Nep4, a critical function of the enzyme's non-catalytic intracellular N-terminus has been demonstrated: when present in excess, the domain induces severe muscle degeneration concomitant with lethality during late larval development. Because the intracellular domain interacts with a carbohydrate kinase, impaired energy metabolism has been proposed as the underlying cause of the phenotype (Panz et al, 2012). In addition, Nep2 has been implicated in the regulation of locomotion and geotactic behavior (Bland et al, 2009), and neprilysin activity in general appears to be critical to the formation of middle- and long-term memory (Turrel et al, 2016), as well as to the regulation of pigment dispersing factor (PDF) signaling within circadian neural circuits (Isaac et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Hallier

Schiemann

Cordes

et al. 2016

eLife

Self Cite

View full text Add to dashboard Cite

Insulin and IGF signaling are critical to numerous developmental and physiological processes, with perturbations being pathognomonic of various diseases, including diabetes. Although the functional roles of the respective signaling pathways have been extensively studied, the control of insulin production and release is only partially understood. Herein, we show that in Drosophila expression of insulin-like peptides is regulated by neprilysin activity. Concomitant phenotypes of altered neprilysin expression included impaired food intake, reduced body size, and characteristic changes in the metabolite composition. Ectopic expression of a catalytically inactive mutant did not elicit any of the phenotypes, which confirms abnormal peptide hydrolysis as a causative factor. A screen for corresponding substrates of the neprilysin identified distinct peptides that regulate insulin-like peptide expression, feeding behavior, or both. The high functional conservation of neprilysins and their substrates renders the characterized principles applicable to numerous species, including higher eukaryotes and humans.

show abstract

Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Hallier

Schiemann

Cordes

et al. 2016

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specificity of immunoreactivity was controlled by incubating specimens in the same manner, but omitting the primary antibodies. Western blots were done essentially as described previously (Panz et al, 2012). Subsequent to homogenization (glass-Teflon homogenizer) and boiling (3 min, 99°C), total protein extracts (10 μg per lane) were separated by SDS-PAGE (17%) and transferred to nitrocellulose membranes (Carl Roth, Karlsruhe, Germany).…”

Section: Immunohistochemistry and Western Blotmentioning

confidence: 99%

Ammonia excretion in the marine polychaeteEurythoe complanata(Annelida)

Thiel

Hugenschütt

Meyer

et al. 2016

Journal of Experimental Biology

Self Cite

View full text Add to dashboard Cite

Ammonia is a toxic waste product from protein metabolism and needs to be either converted into less toxic molecules or, in the case of fish and aquatic invertebrates, excreted directly as is. In contrast to fish, very little is known regarding the ammonia excretion mechanism and the participating excretory organs in marine invertebrates. In the current study, ammonia excretion in the marine burrowing polychaete Eurythoe complanata was investigated. As a potential site for excretion, the 100-200 µm long, 30-50 µm wide and up to 25 µm thick dentrically branched, well ventilated and vascularized branchiae (gills) were identified. In comparison to the main body, the branchiae showed considerably higher mRNA expression levels of Na + /K + -ATPase, V-type H + -ATPase, cytoplasmic carbonic anhydrase (CA-2), a Rhesus-like protein, and three different ammonia transporters (AMTs). Experiments on the intact organism revealed that ammonia excretion did not occur via apical ammonia trapping, but was regulated by a basolateral localized V-type H + -ATPase, carbonic anhydrase and intracellular cAMP levels. Interestingly, the V-type H + -ATPase seems to play a role in ammonia retention. A 1 week exposure to 1 mmol l −1 NH 4 Cl (HEA) did not cause a change in ammonia excretion rates, while the three branchial expressed AMTs showed a tendency to be down-regulated. This indicates a shift of function in the branchial ammonia excretion processes under these conditions.

show abstract

Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides

et al. 2022

Self Cite

View full text Add to dashboard Cite

Muscle contraction depends on strictly controlled Ca2+ transients within myocytes. A major player maintaining these transients is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, SERCA. Activity of SERCA is regulated by binding of micropeptides and impaired expression or function of these peptides results in cardiomyopathy. To date, it is not known how homeostasis or turnover of the micropeptides is regulated. Herein, we find that the Drosophila endopeptidase Neprilysin 4 hydrolyzes SERCA-inhibitory Sarcolamban peptides in membranes of the sarcoplasmic reticulum, thereby ensuring proper regulation of SERCA. Cleavage is necessary and sufficient to maintain homeostasis and function of the micropeptides. Analyses on human Neprilysin, sarcolipin, and ventricular cardiomyocytes indicates that the regulatory mechanism is evolutionarily conserved. By identifying a neprilysin as essential regulator of SERCA activity and Ca2+ homeostasis in cardiomyocytes, these data contribute to a more comprehensive understanding of the complex mechanisms that control muscle contraction and heart function in health and disease.

show abstract

A novel role for the non‐catalytic intracellular domain of Neprilysins in muscle physiology

Cited by 9 publications

References 54 publications

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Ammonia excretion in the marine polychaeteEurythoe complanata(Annelida)

Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides

Contact Info

Product

Resources

About