Abstract
Background Receptors for the natriuretic peptides (NPs) ANP, BNP and CNP are highly expressed in lung, suggesting that this organ is an important physiological target for NP signalling. By stimulating vasoand bronchodilation and inhibiting cell proliferation and fibrotic processes, NPs may have therapeutic potential in various lung diseases. Mechanisms responsible for the relatively short half-life (few min) of NPs and the control of their local concentrations include (i) receptor-mediated internalization by the so called clearance receptor (NPR-C) and (ii) degradation by a membrane metalloprotease, called neutral endopeptidase (NEP) or neprilysin (1). The velocity of peptide degradation/inactivation differs between ANP, BNP and CNP. Interestingly, cleavage of NPs by insulindegrading enzyme (IDE) (2) may have a particular role in NP signalling by generating peptide fragments that are hyperactive in receptor stimulation (3). The physiological significance of NEP was supported by several studies in rodents showing that NEP inhibition leads to increased NP concentrations and activity. Moreover, we found that NEP inhibition is necessary and sufficient for detection of GC-A and GC-B by affinity labelling experiments with radioactive ANP or CNP in mouse and rat lung membrane preparations. Analogous assays, however, failed to label these receptors in human lung membranes, suggesting potent NP-degrading activity of NEP inhibitor-insensitive proteases.
Highlights
Receptors for the natriuretic peptides (NPs) ANP, BNP and CNP are highly expressed in lung, suggesting that this organ is an important physiological target for NP signalling
The physiological significance of neutral endopeptidase (NEP) was supported by several studies in rodents showing that NEP inhibition leads to increased NP concentrations and activity
We found that NEP inhibition is necessary and sufficient for detection of GC-A and GC-B by affinity labelling experiments with radioactive ANP or CNP in mouse and rat lung membrane preparations
Summary
Receptors for the natriuretic peptides (NPs) ANP, BNP and CNP are highly expressed in lung, suggesting that this organ is an important physiological target for NP signalling. The velocity of peptide degradation/inactivation differs between ANP, BNP and CNP. Cleavage of NPs by insulindegrading enzyme (IDE) (2) may have a particular role in NP signalling by generating peptide fragments that are hyperactive in receptor stimulation (3). The physiological significance of NEP was supported by several studies in rodents showing that NEP inhibition leads to increased NP concentrations and activity. We found that NEP inhibition is necessary and sufficient for detection of GC-A and GC-B by affinity labelling experiments with radioactive ANP or CNP in mouse and rat lung membrane preparations. Analogous assays failed to label these receptors in human lung membranes, suggesting potent NP-degrading activity of NEP inhibitor-insensitive proteases
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