Natriuretic peptide metabolism, clearance and degradation

Abstract

Atrial natriuretic peptide, B-type natriuretic peptide and C-type natriuretic peptide constitute a family of three structurally related, but genetically distinct, signaling molecules that regulate the cardiovascular, skeletal, nervous, reproductive and other systems by activating transmembrane guanylyl cyclases and elevating intracellular cGMP concentrations. This review broadly discusses the general characteristics of natriuretic peptides and their cognate signaling receptors, and then specifically discusses the tissue-specific metabolism of natriuretic peptides and their degradation by neprilysin, insulin-degrading enzyme, and natriuretic peptide receptor-C.

Figure 1

Natriuretic peptides bind multiple cell surface proteins. Bolded black natriuretic peptide abbreviations indicate binding or substrate preference. NPR-C internalizes all three natriuretic peptides, which targets them for degradation by intracellular proteases. NEP is an extracellular metalloprotease that cleaves ANP and CNP at the C-F bond and breaks the ring. BNP is a much poorer substrate for NEP and is not cleaved at the conserved C-F bond. Insulin degrading enzyme (IDE) is depicted as a cytosolic enzyme but it has also been found in membrane preparations [64]. It initially cleaves ANP and BNP outside the ring.

Figure 2

Initial NEP and IDE cleavage sites in human natriuretic peptides. NEP data are from studies by Kenny et al, Vanneste et al, Norman et al and Watanabe et al. [49, 50, 53, 55]. IDE cleavage sites are from studies performed by Muller et al using rat brain IDE and rat ANP, porcine BNP-26 and porcine CNP and Ralat et al using recombinant human IDE and human natriuretic peptides [68, 69]. Large blue arrows indicates primary initial IDE sites. The small blue arrow indicates a minor initial IDE site in ANP. Both groups observed IDE cleavage of CNP between D¹² and R¹³ but only Ralat et al observed cleavage between S³ and K⁴.