exenatide and heliodermin

Exendins are secretin hormone-like peptides that are components of the toxins from two venomous lizards, Heloderma suspectum (Gila monster) and Heloderma horridium (Mexican bearded lizard). Exendins-1 and -2 are vasoactive intestinal peptide (VIP)-like, both in sequence and function, while exendins-3 and -4 are glucagon-like peptide-1 (GLP-1)-like. The evolutionary origin of these peptides, and the genes that encode them, has been unclear. Recently, genes orthologous to exendin have been identified in reptiles, birds and amphibians. Analysis of the orthologous sequences demonstrates that the Heloderma exendins diversified by gene duplication from a common exendin ancestor on the Heloderma lineage after divergence from other reptiles, including the anole lizard and Burmese python. In addition, the exendin toxin peptide sequences, but not their pro or signal peptides, have evolved very rapidly on the Heloderma lineage, likely as they adapted to their new function as toxins. Exendins-1 and -2 not only evolved rapidly but their sequences have evolved convergently upon that of VIP, resulting in a doubling of its identity with VIP, while exendins-3 and -4 have retained an ancestral property of being more GLP-1-like sequences. These results suggest that the ancestral role of exendin, which is potentially still retained in some species, had greater similarity with proglucagon-derived peptides or GIP.

Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Exenatide; Intercellular Signaling Peptides and Proteins; Lizards; Molecular Sequence Data; Peptides; Phylogeny; Venoms; Vertebrates

Topics: Amino Acid Sequence; Animals; Exenatide; Humans; Intercellular Signaling Peptides and Proteins; Lizards; Molecular Sequence Data; Peptides; Venoms

Vasoactive intestinal polypeptide (VIP) is known as an important regulator of airway function. It has been suggested that VIP is involved in the pathogenesis of asthma due to its relaxant effects on smooth muscles. The present study was designed to characterize the effects of the peptides of the VIP family on airway mucus secretion. The peptides VIP, PHI, PACAP-27, PACAP-38, GLP-I, exendin-4, helodermin, helospectin I and helospectin II were investigated using isolated rat trachea. Data show that PACAP-27 is the most potent stimulator of airway mucus secretion (225% stimulation). The rank order of potency was PACAP-27 > VIP > helospectin II > PHI > exendin-4 = helodermin = helospectin I = PACAP-38. The addition of the protease inhibitor thiorphan enhanced the effects of PHI and helodermin, but not of the other peptides. These data show that the peptides of the VIP family stimulate airway mucus secretion differently.

Topics: Animals; Exenatide; Glucagon; Glucagon-Like Peptide 1; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Male; Mucus; Neuropeptides; Peptide Fragments; Peptide PHI; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Protease Inhibitors; Protein Precursors; Rats; Rats, Sprague-Dawley; Thiorphan; Trachea; Vasoactive Intestinal Peptide; Venoms

Helodermin and exendin-4, two peptides isolated from the salivary gland of the Gila monster, Heloderma suspectum, are approximately 50% homologous to vasoactive intestinal peptide (VIP) and glucagon-like peptide-1 (GLP-1), respectively, and interact with the mammalian receptors for VIP and GLP-1 with equal or higher affinity and efficacy. Immunohistochemical studies suggested the presence of helodermin-like peptides in mammals. To determine whether helodermin and exendin-4 are present in mammals and their evolutionary relationship to VIP and GLP-1, their cDNAs were first cloned from Gila monster salivary gland. Northern blots and reverse transcription-polymerase chain reaction of multiple Gila monster tissues identified approximately 500-base pair transcripts only from salivary gland. Both helodermin and exendin-4 full-length cDNAs were approximately 500 base pairs long, and they encoded precursor proteins containing the entire amino acid sequence of helodermin and exendin-4, as well as a 44- or 45-amino acid N-terminal extension peptide, respectively, having approximately 60% homology. The size and structural organization of these cDNAs indicated that they were closely related to one another but markedly different from known cDNAs for the VIP/GLP-1 peptide family previously identified in both lower and higher evolved species. Cloning of the Gila monster VIP/peptide histidine isoleucine, pituitary adenylate cyclase activating polypeptide, and glucagon/GLP-1 cDNAs and Southern blotting of Gila monster DNA demonstrate the coexistence of separate genes for these peptides and suggests, along with the restricted salivary gland expression, that helodermin and exendin-4 coevolved to serve a separate specialized function. Probing of a variety of rat and human tissues on Northern blots, human and rat Southern blots, and genomic and cDNA libraries with either helodermin- or exendin-4-specific cDNAs failed to identify evidence for mammalian homologues. These data indicate that helodermin and exendin-4 are not the precursors to VIP and GLP-1 and that they belong to a separate peptide family encoded by separate genes. Furthermore, the existence of as yet undiscovered mammalian homologues to helodermin and exendin-4 seems unlikely.

Topics: Amino Acid Sequence; Animals; Base Sequence; Chickens; Cloning, Molecular; DNA Primers; DNA, Complementary; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Intercellular Signaling Peptides and Proteins; Lizards; Mammals; Molecular Sequence Data; Neuropeptides; Peptide Fragments; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Polymerase Chain Reaction; Protein Precursors; Rats; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Trout; Vasoactive Intestinal Peptide; Venoms