Helodermin is a peptide that shows a high degree of sequence similarity with vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and secretin in its N-terminal moiety.
In 1982, it was observed that the venom from Gila monster exerts a potent secretory effect on dispersed pancreatic acini from guinea pig. Moreover, the venom causes a 50-fold increase in increase in cellular cAMP and inhibited binding of 125I-vasoactive intestinal peptide to its membrane receptors on pancreatic acini. These results indicate that venom from Gila monster contains a peptide helodermin, which can stimulate pancreatic enzyme secretion by interacting with vasoactive intestinal peptide receptors on pancreatic acinar cells and thereby activating adenylate cyclase and increasing cellular cAMP1.
The complete amino acid sequence of helodermin isolated from the venom of Gila monster has been elucidated. The peptide has shown to be a basic pentatriacontapeptide amide: His-Ser-Asp-Ala-Ile-Phe-Thr-Gln-Gln-Tyr-Ser-Lys-Leu-Leu-Ala-Lys-Leu-Ala-Leu-Gln-Lys-Tyr-Leu-Ala-Ser-Ile-Leu-Gly-Ser-Arg-Thr-Ser-Pro-Pro-Pro-NH2. A high degree of sequence similarities to secretin/ VIP/ PHI/ (PHM)/ GRF from mammal and bird was observed over the entire N-terminal 1–27 sequence. Another interesting feature of the structure of helodermin was its C-terminal -Pro-Pro-Pro-NH2 sequence2.
In comparison with other members of the secretin/VIP family of peptides, helodermin has an unusually stable secondary structure, partly owing to a secondary configuration it maintains in water, which may account for its prolonged physiological action 3.
Helodermin, helospectin, and PACAP stimulate cyclic AMP formation in intact bone, isolated osteoblasts, and osteoblastic cell lines - Helodermin and helospectin isolated from the salivary gland venom of the lizard Heloderma suspectum and Pituitary adenylate cyclaseactivating polypeptide (PACAP) isolated from ovine hypothalamus shows sequence homology to vasoactive intestinal peptide (VIP). In a study, lizard helodermin was found to cause a time- and dose-dependent stimulation of cyclic AMP (cAMP) formation in neonatal mouse calvarial bones. Also, helospectin I, PACAP 27, and the C-terminally extended PACAP 38 stimulated cAMP accumulation in the mouse calvariae. The cAMP rise in response to helodermin was comparable to that induced by VIP, both in terms of potency and magnitude of the response. Helodermin, helospectin I, PACAP 27, and PACAP 38, at concentrations of 1 mol/liter, stimulated cAMP accumulation in enzymatically isolated mouse calvarial bone cells. A significant response to all peptides was observed in both early and late released bone cells isolated from the calvariae, with low and high alkaline phosphatase activity, respectively. Helodermin and VIP stimulated cAMP accumulation in the cloned mouse calvarial osteoblastic cell line MC3T3-E1, in rat (UMR 106-01), and human (Saos-2) osteoblastic osteosarcoma cell lines, but not in the rat osteosarcoma cell line ROS 17/2.8. The effect of helodermin was synergistically and dose-dependently enhanced by forskolin (0.1 and 1 mol/liter). These data show that bone cells, including osteoblasts, respond to several peptides of the VIP family, including helodermin, helospectin I, PACAP 27, and PACAP 38 4.
Helodermin produced Glibenclamide-sensitive hypotension in the rat- The effects of helodermin, on arterial blood pressure and heart rate were examined in the rat, focusing on the possibility that activation of ATP sensitive K+ (K(ATP)) channels is involved in the responses. Helodermin produced hypotension in a dose-dependent manner with approximately similar potency and duration when to compare with those of vasoactive intestinal polypeptide (VIP). These findings suggest that helodermin-produced hypotension is partly attributable to the activation of glibenclamide-sensitive K+ channels (K (ATP) channels), which presumably exist on arterial smooth muscle cells5.
Helodermin-like peptides stimulate thyroid hormone secretion and suppression of calcium incorporation into bone- Helodermin-like immunofluorescence was observed in the parafollicular (C) cells in several mammals and in the C cell homologues of the chicken ultimobranchial gland. Helodermin stimulated basal thyroid hormone secretion and colloid droplet formation in conscious mice. The effect of large doses of helodermin was quite long-lasting and the maximal response occurred after 2 - 6 hr. In addition, helodermin suppressed the incorporation of calcium into bone in conscious rats. These findings suggest that helodermin-like peptides in C cells may be involved in the local regulation of thyroid hormone secretion and in the maintenance of calcium homeostasis6.
1. Raufman, J P, Jensen RT, Sutliff V E., Pisano J J and Gardner J D (1982). Actions of Gila monster venom on dispersed acini from guinea pig pancreas. Am. J. Physiol., 242, G470-G474.
2. Hoshino M, Yanaihara C, Hong Y M, Kishida S, Katsumara Y, Vandermeers A, Vandermeers-Piret M-C, Robberecht P, Christophe J & Yanaihara N (1984). Primary structure of helodermin, a VIP-like peptide isolated from the Gila monster venom. FEBS Lett 178: 233-239.
3. Wulf Blankenfeldt, Kiyoshi Nokihara, Satoru Naruse, Uta Lessel, Dietmar Schomburg, and Victor Wray (1996). NMR Spectroscopic Evidence That Helodermin, unlike Other Members of the Secretin /VIP Family of Peptides, Is Substantially Structured in Water Biochemistry., 35 (19), 5955–5962.
4. U. H. Lerner, P. Lundberg, M. Ransjö, P. Perssonand R (1994). Hakanson Helodermin, helospectin, and PACAP stimulate cyclic AMP formation in intact bone, isolated osteoblasts, and osteoblastic cell lines. Calcified Tissue International., 54: 284-289
5. N Horikawa, K Kataha, N Watanabe, K Ishii, N Yanaihara, Y Tanaka, K Shigenobu, K Nakayama (1998). Biological & pharmaceutical bulletin 21: 1290-3.
6. T Grunditz, P Persson, R Hakanson, A Abosood, G Bottcher, C Rerup and Sundler (1989). Proc. NatI. Acad. Sci., 86: 1357-1361.
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