In order for the NPR-A receptor to become activated, ANP and BNP must first be adequately processed into biologically active peptides. For example, BNP is produced as a 126 amino acid precursor molecule, and after the secretion signal is removed, proBNP exists as an 108 amino acid molecule. ProBNP (BNP1-108) is cleaved in a highly sequence-specific manner into a 32 amino acid, carboxyl fragment (BNP-32) and a 76 amino acid amino terminal fragment (NT-BNP).
Recently the major enzyme responsible for the processing of proANP and proBNP has been identified to be corin, a type II trans-membrane serine protease predominantly expressed by cardiomyocytes(32
); therefore, corin appears to be the long sought after “NP convertase”. The current paradigm suggests that after synthesis in ventricular cardiomyocytes, BNP is not stored, but rather targeted for secretion using the large dense-core vesicle (LDCV) pathway characteristic of neurotransmittor secretion and secretion of other peptide hormones(33
). According to the present hypothesis, BNP 1-108 is then released from cardiomyocytes and interacts with corin's extracellular catalytic domain whereupon it is cleaved into BNP-32 and NT-BNP. () Even in the case of ANP that is stored in atrial secretory granules, the ANP stored in the secretory granules is thought to be unprocessed proANP, and corin is thiught to participates in extracellular proANP cleavage upon exocytosis from atrial secretory granules. Some investigators have also suggested that furin, a ubiquitously expressed serine endopeptidase, may participate in intracellular BNP processing, but this remains controversial and an active area of research(34
). However, corin is clearly one of the most significant contributors to natriuretic peptide processing as evidenced by the murine corin knockout model(36
). The corin knockout mice as compared to controls develop salt-sensitive hypertension and cardiac hypertrophy, with evidence of circulating unprocessed proANP. Administration of activated soluble corin results in a rapid decline in proANP, increase in plasma cGMP and lowering of systemic blood pressure.
Figure 1 ProBNP is produced in cardiomyocytes where it is not stored but rapidly targeted for secretion after removal of the targeting sequence. Our current paradigm suggests that BNP 1-108 is released from ventricular cardiomyocytes and interacts with the extracellular (more ...)