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Definition
Physalaemin-like peptides group is represented in the amphibian skin by the following three members - Physalaemin, Phyllomedusin and Uperolein. Two important physalaemin-like peptides occur outside the amphibian skin: eledoisin and substance P (SP).

Discovery
Physalaemin, the prototype of the group, first isolated in a pure form from methanol extracts of the skin of Physalaemus bigilonigerus (fuscumaculatus) and is also present in skin extracts of other Physalaemus species as well (Physalaemus centralis, Physalaemus bresslaui)1. Phyllomedusin, isolated from methanol extracts of the skin of the Amazonian hylid frog Phyllomedusa bicolor 2. Uperolein, found in the skin of Australian amphibians belonging to the genera Uperoleia and probably also Taudactylus. Eledoisin was discovered in the salivary glands of certain Mediterranean species of octopus3. SP was discovered in 1931 by von Euler and Gaddum as a tissue extract that caused intestinal contraction in vitro4.

Structural Charachterisics
Physalaemin-like peptide belong to tachykinin (TKs) peptide family. Bio-assay and chemical analysis showed that physalaemin is closely related to elodoisin, both from a biological and chemical point of view5. Two physalaemin (PHY)-like immunoreactive peptides reflects homology at amino acid residues 1, 3, 4 and 5 for the mammalian and amphibian residues 6. Uperolein which is an  physalaemin-like endecapeptide, has been shown to be selective for Neurokinin 1 receptor. Analysis of NMR data indicates that the global fold of Uperolein can be explained in terms of equilibrium between 310-helix and alpha-helix from residues 5 to 11. An extended highly flexible N-terminus displays some degree of order and a possible turn structure. A comparison between the structures of Uperolein and SP, a prototype and endogenous Neurokinin 1 receptor agonist, indicates several common features in the distribution of hydrophobic and hydrophilic residues. Both the peptides show an amphiphilic character towards the middle region. The similarities suggest that the molecules interact with the receptor in an analogous manner7.

The sequence of physalaemin is Pyr-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Gly-Leu-Met-NH2.

The sequence of Phyllomedusin is Pyr-Asn-Pro-Asn-Arg-Phe-Ile-Gly-Leu-Met-NH2

The sequence of Uperolein is Pyr-Pro-Asp-Pro-Asn-Ala-Phe-Tyr-Gly-Leu-Met-NH2.

The sequence of Eledoisin is Pyr-Pro-Ser-Lys-Asp-Ala-Phe-Ile-Gly-Leu-Met-NH2

The sequence of SP is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2


Mode of action
The striking hypotensive effects of the tachykinins observed in some animal species, as a consequence of intense vasodilation in several peripheral vascular beds, must be considered a direct effect of the peptides on the blood vessel wall.  The site of action of the tachykinins is endothelium of the blood vessel. Thus tachykinins may act to promote the release of endogenous factors from the endothelium that is able to reduce the tone of the arterial smooth muscle fibers. The SP receptor is a G protein-coupled receptor, in many respects similar to other well-studied receptors in psychiatry, particularly monoamine receptors .  The interaction of SP with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with SP, there is scope for numerous therapeutic possibilities 8.

Functions
TKs display a number of potent pharmacological actions in the periphery and in the central nervous system. Eledoisin, kassinin, and, to a lesser extent, physalaemin caused release of vasopressin, with ensuing antidiuresis. In dogs Physalaemin was very effective in antagonizing the pressor effects of noradrenaline and angiotensin II given at doses 100 and 10 times higher, respectively.In human volunteers, eledoisin given by rapid intravenous injection (threshold 15–20 pmol/kg) decreased blood pressure, caused spinal fluid hypertension, increased the rate of respiration and caused skin vasodilation, particularly in the head. Physalaemin and, to a considerably lesser extent eledoisin and SP (Losay et al., 1977) displayed a very potent vasodilator action9. Eledoisin infused intravenously in the dog at 0.01 nmol/kg/min decreased cerebral blood flow (−22%), with an increase (+20%) in vascular resistance (Beretta Anguissola et al., 1966)10.

References

1.     Anastasi A, Erspamer V, Cei JM (1964). Isolation and amino acid sequence of physalaemin, the main active polypeptide of the skin of Physalaemus fuscumaculatus. Arch Biochem Biophys., 108:341-348.

2.     Anastasi A, Erspamer GF (1970). Occurrence of phyllomedusin, a physalaemin-like decapeptide, in the skin of Phyllomedusa bicolor. Experientia., 26(8):866-867.

3.     Jaeger W (1988). Treatment of a severe course of keratoconjunctivitis sicca with eledoisin. Klin Monbl Augenheilkd.,192(2)163-166.

4.    Senba E, Tohyama M (1985). Origin and fine structure of substance P-containing nerve terminals in the facial nucleus of the rat:an immunohistochemical study. Exp Brain Res., 57(3):537-546.

5.     Bernardi L, Bosisio G, Goffredo O, De Castiglione R (1964). Synthesis of physalaemin. Experientia., 20(9):490-492.

6.     Dike A, Cowsik SM (2006). Solution structure of amphibian tachykinin Uperolein bound to DPC micelles. J Struct Biol., 156(3):442-52.

7.     Wilson WE, Harvan DJ, Hamm C, Lazarus LH, Klapper DG, Yajima H, Hayashi Y (1986). Physalaemin-like immunoreactive peptides from rabbit stomach. Int J Pept Protein Res. 28(1):58-66.

8.     Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V (2002). The tachykinin peptide family. Pharmacol Rev., 54(2):285-322.

9.   Losay J, Mroz E, Tregear GW, Leeman SE, Gamble WJ (1977. Action of substance P on the coronary blood flow in the isolated dog heart. in Substance P. Raven Press, New York, 287–293.

10. Beretta Anguissola A, Feruglio FS, Campus S, Chiandussi L, Pandolfo G, Berti G (1966). The effects of eledoisin and bradykinin on the general and visceral circulation. in Hypotensive Peptides, Springer-Verlag, New York, 430–440.

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