Moving pieces in a cryptomic puzzle: Cryptide from Tityus serrulatus Ts3 Nav toxin as potential agonist of muscarinic receptors

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2017-12, Vol.98, p.70-77
• Main Authors: Rocha-Resende, Cibele, Leão, Nádia Miricéia, de Lima, Maria Elena, Santos, Robson Augusto, Pimenta, Adriano Monteiro de Castro, Verano-Braga, Thiago
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Bradykinin receptor; Bradykinin-potentiating peptides; Humans; Male; Models, Animal; Muscarinic acetylcholine receptor; Peptidyl-Dipeptidase A - drug effects; Rats; Rats, Wistar; Receptor, Muscarinic M2 - agonists; Receptor, Muscarinic M3 - agonists; Scorpion Venoms - pharmacology; Tityus serrulatus; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Voltage-Gated Sodium Channels - drug effects
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2016.12.018

•The primary structure of Ts10 is highly similar to the N-terminal of the neurotoxin Ts3.•Similar to Ts10, Ts3 N-terminus (named Ts31-14[C12S]) is also a vasoactive peptide.•Unlike previously reported, Ts10 is not an ACE inhibitor.•Ts10 and Ts31-14[C12S] are potential agonists of muscarinic acetylcholine receptors. Cryptome is as a subset of a given proteome containing bioactive cryptides embedded in larger peptides or proteins. We pinpointed a striking sequence similarity between two peptides from the Tityus serrulatus venom: Ts10 (KKDGYPVEYDRAY) and the N-terminal of Ts3 (KKDGYPVEYDNCAY). Ts3 (former Tityustoxin or TsIV) is an α-neurotoxin acting on voltage-gated sodium channels while Ts10 (former Peptide T) is a bradykinin-potentiating peptide and was originally reported as inhibitor of the angiotensin-converting enzyme (ACEi). Thus, the goal of this study was to evaluate whether such peptide hidden in the N-terminal of Ts3 (Ts31-14[C12S]) was able to mimic known effects of Ts10 as well as to expand the current knowledge of the vascular effects and molecular targets of these peptides. Similar to Ts10, Ts31-14[C12S] was able to potentiate the hypotensive effect of bradykinin (BK). However, none of these peptides was able to induce a long-lasting BK-potentiating effect, suggesting that this effect may not be their main biological outcome. On the other hand, we report that Ts10 and mainly Ts31-14[C12S] induced a strong vasodilation effect depending on the presence of functional endothelium and nitric oxide (NO) production. Unlike previously reported, Ts10 was not able to inhibit ACE activity (similar result was observed for Ts31-14[C12S]). On the other hand, we report that Ts31-14[C12S] induces vasodilation via the activation of muscarinic acetylcholine receptors (mAChRs) M2 and M3 while only the activation of mAChR M2 seems to be required for Ts10-induced vasodilation.