Tail wags the dog: Activity of krait natriuretic peptide is determined by its C-terminal tail in a natriuretic peptide receptor-independent manner
Natriuretic peptides (NP) are potent vasoactive hormones, which maintain pressure-volume homeostasis. Snake venom NPs exhibit distinct biological activity compared to mammalian NPs due to subtle changes in their sequences. We recently identified a new NP from krait venom (KNP), with an unusual 38-residue long C-terminal tail, which has a propensity to form an α-helix. KNP mediates vasodilation via NP receptor (NPR) independent mechanisms on pre-contracted aortic strips in contrast to classical NPs. The infusion of KNP in anesthetized rats resulted in a prolonged and sustained drop in blood pressure and heart rate with no renal effects in contrast to mammalian counterparts. Deletion mutant studies have revealed the presence of two functional segments in KNP, namely Ring and Helix. Although the Ring interacts with NPR, its contribution to the activity of KNP is shown to be negligible as both KNP and Helix elicit equipotent endothelium-dependent vasorelaxation. Further, KNP and Helix signaled through endothelial nitric oxide to mediate NPR-independent vasodilation. Thus, KNP exhibits non-canonical characteristics through its C-terminal tail, despite a functional NP ring. This study has altered the paradigm of NP biology through the understanding of structure-function relationships and may serve as a lead for the design of novel hypotensive agents.
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