Natriuretic peptide family
Natriuretic peptides (NP) are body fluid volume modulators, termed natriuretic peptides due to a role in
. There are various NP peptides which vary in length but which have a common central core. The mammalian NPs include
atrial or A-type natriuretic peptide (ANP)
brain or B-type natriuretic peptide (BNP)
C-type natriuretic peptide (CNP)
. In addition, NPs have been discovered in many other vertebrates including amphibians, reptiles and fish, with plants and, more recently, bacteria also being found to possess homologous NPs.
All NPs possess a 17-residue ring structure with a highly conserved internal sequence and exert their biological effects by binding to membrane-bound receptors (
). NPR1 and NPR2 are membrane-bound receptors with guanylyl cyclase activity, and mediate the majority of the biological effects of NPs. The primary role of NPR3 is the clearance of circulating NPs through receptor mediated internalization and degradation.
The mechanisms of clearance include binding to cell surface clearance receptors (NPR3) with subsequent cellular internalization and lysosomal degradation, proteolytic cleavage by endopeptidases such as
and renal filtration. Neprilysin hydrolyses peptide bonds at the amino side of hydrophobic residues, thereby inactivating NPs by opening their 17-residue ring structure. NPs with extended N- and C-terminal tails have shown greater resistance to neprilysin hydrolysis.
ANP and BNP both bind to NPR1 with high affinity, while CNP is the primary ligand for NPR2. All three NPs bind to NPR3 in the order ANP > CNP ?≥ BNP (
Bennett et al., 1991
In reptilian venom
NPs from reptilian venoms are structural and functional equivalents of mammalian NPs. The potent hypotensive effect produced by NPs contributes to a rapid loss of consciousness in envenomated animals. One of the first reptilian NPs discovered was
Dendroaspis natriuretic peptide (DNP)
, which was isolated from the venom glands of Dendroaspis angusticeps. DNP is a potent natriuretic and diuretic peptide, which, like ANP and BNP, is associated with an increase in urinary and plasma cGMP. This peptide was also found to have greater stability to
than the three mammalian NPs, which is most likely attributed to the elongated N-and C-terminal tails. This discovery, in particular the high potency that was observed, prompted the utilization of reptilian venom for the identification of novel NPs.
Unusual NP activities have been found in snake venom peptides in which the amino acid sequence is homologous to the NP family. Some of these include inhibition of platelet aggregation displayed by
and ACE inhibition exhibited by
. In some cases, these peptides lack the cGMP-stimulating activity responsible for natriuresis and diuresis, suggesting that they could be used to identify important residues for NPR1 binding and activation.
Reptilian venom natriuretic peptides are encoded by large precursor polypeptides that typically contain an open-reading frame encoding (i) numerous, tandemly arranged, distinct
bradykinin-potentiating peptides (BPPs)
flanked by conserved spacer regions and (ii) at the C-terminus, a C-type natriuretic peptide (CNP). These multi-component transcripts have been termed BPP-CNP precursors.
Related protein family
Bradykinin potentiating peptides
that are partly released from BPP-natriuretic peptide precursors.
This protein family in
Vink et al., 2012
SIB Swiss Institute of Bioinformatics