Cottus scorpius, the archaic gar-pike Lepisosteus
spatula (Holostei), and the skate Torpedo marmorata all produce only one glucagon and one GLP.
Mammals, and also lower vertebrates such as the
bullfrog Rana catesbeiana and Lepisosteus spatula, possess not only glucagon and GLP but also
the somewhat longer oxyntomodulin (36 amino
acids), which is made up of the glucagon
sequence and a C-terminal extension; this peptide is 5- to lO-fold less active than glucagon on
liver cell membranes but is approximately 20-fold
more effective on stomach mucous membranes
[170]. Analysis of the prepro-glucagon sequences
suggests that GLP-2 arose from glucagon about
1200 million years ago and GLP-l about 800 million years ago, and that in fish the GLP-2 was lost
before duplication of the glucagon gene.
Glucagon is a highly conserved polypeptide;
with the exception of the guinea-pig, the sequences of all mammals to have been examined are
identical. The chicken and turkey differ from the
mammalian sequence at only one position, the
duck at two positions, the shark Scyliorhynchus
canicula at four positions, and the coho salmon
Oncorhynchus kisutch at eight positions [3]. The
GLPs are evolving rather more rapidly: the GLP1 sequenced from Ictalurus differs from the two
GLPs of the angler fish Lophius in 5 and 9 out of
34 amino acids, from the GLP-l ofthe hamster at
11 positions, and from hamster GLP-2 at as many
as 23 positions [3, 38]. In contrast to insulin, the
glucagons in the storage granules of islet cells are
mostly amorphous; only in the teleosts are they
crystalline, probably with a trimeric structure.
Glicentin apparently has trophic functions in the
gut mucosa and may be looked upon as an enteroglucagon. A further GLP, synthesized in the
endocrine L cells of the porcine gut, corresponds
to amino acids 33-69 of glicentin and is referred
to as enteroglucagon II. The special evolutionary position of the guinea-pig gastro-enteropancreatic peptides is as clearly illustrated by
glucagon and VIP as by insulin: whereas all other
mammals have a glucagon of 29 amino acids, the
guinea-pig molecule is 40 amino acids long. Similarly, the VIP sequences of all other mammals are
identical but guinea-pig VIP differs in 4 of the
28 amino acids [55]. The VIP of the chicken also
differs from the typical mammalian sequence at
four positions and those of the cod Gadus morrhua and the shark Scyliorhinus canicula differ at
eight positions [52]. GIP is not quite as highly
conserved, with the human sequence differing in
2 and 4 of 42 amino acids from the porcine and
bovine sequences, respectively [214]. Secretin is a
8.5 Peptides Regulating Blood Pressure
301
peptide of 27 residues that stimulates pancreas
secretion. The rat secretin gene shows homology
only to the other genes of this hormone family in
the exons encoding the bioactive peptide, and the
only translated product is secretin, whereas the
genes for pro-glucagon and pro-VIP each produce
several different bioactive peptides [88, 107].
8.4.4 The Family of Pancreas Polypeptides
The pancreas polypeptide (PP) of the chicken,
discovered in 1975, is a C-terminal amidated peptide of 36 amino acids that functions as an antagonist of glucagon, inhibiting lipolysis in the fat
cells. PP belongs to a family of polypeptides
including peptide YY from the gut wall (PYY)
and from the brain NPY, with which it shows
50-70 % similarity [202, 216]; also included is
peptide YG from the pancreas of the angler fish
Lophius americanus (aPY). The PP-producing
cells are a specific type of endocrine pancreatic
cell distinct from the glucagon-producing A
cells, the insulin-producing B cells and the
somatostatin-producing D cells. The human,
sheep and cat PP precursor includes a C-terminal
20-residue peptide that is absent in the rat and the
mouse. The guinea-pig, whose insulin and glucagon differ markedly from those of other mammals, produced a PP precursor with 89 % agreement to the human molecule in the hormone
region but with only 40 % similarity in the icosapeptide part [15,244]. The aPY precursor is
identical in structure to that of PP. The 64 % similarity of the active peptide of aPY with PP and
NPY is much greater than the agreement between
the remaining regions; this is comparable with the
higher rate of evolution of the insulin C peptide
compared with the A and B chains [7]. PPs have
been reported from many vertebrate species and
have 9 out of 36 invariant residues [125, 171]. PPlike substances have also been detected in annelids and insects.
8.5 Peptides Regulating Blood Pressure
The juxtaglomerular cells situated in the kidney
glomeruli release renin in response to a decrease
in blood pressure or to sodium deficiency. Renins
are found in several forms; as well as in the kidneys, they are produced in the salivary glands and
in the female genital tract. They are all glycoproteins of about 40 kDa, made up of two chains
spatula (Holostei), and the skate Torpedo marmorata all produce only one glucagon and one GLP.
Mammals, and also lower vertebrates such as the
bullfrog Rana catesbeiana and Lepisosteus spatula, possess not only glucagon and GLP but also
the somewhat longer oxyntomodulin (36 amino
acids), which is made up of the glucagon
sequence and a C-terminal extension; this peptide is 5- to lO-fold less active than glucagon on
liver cell membranes but is approximately 20-fold
more effective on stomach mucous membranes
[170]. Analysis of the prepro-glucagon sequences
suggests that GLP-2 arose from glucagon about
1200 million years ago and GLP-l about 800 million years ago, and that in fish the GLP-2 was lost
before duplication of the glucagon gene.
Glucagon is a highly conserved polypeptide;
with the exception of the guinea-pig, the sequences of all mammals to have been examined are
identical. The chicken and turkey differ from the
mammalian sequence at only one position, the
duck at two positions, the shark Scyliorhynchus
canicula at four positions, and the coho salmon
Oncorhynchus kisutch at eight positions [3]. The
GLPs are evolving rather more rapidly: the GLP1 sequenced from Ictalurus differs from the two
GLPs of the angler fish Lophius in 5 and 9 out of
34 amino acids, from the GLP-l ofthe hamster at
11 positions, and from hamster GLP-2 at as many
as 23 positions [3, 38]. In contrast to insulin, the
glucagons in the storage granules of islet cells are
mostly amorphous; only in the teleosts are they
crystalline, probably with a trimeric structure.
Glicentin apparently has trophic functions in the
gut mucosa and may be looked upon as an enteroglucagon. A further GLP, synthesized in the
endocrine L cells of the porcine gut, corresponds
to amino acids 33-69 of glicentin and is referred
to as enteroglucagon II. The special evolutionary position of the guinea-pig gastro-enteropancreatic peptides is as clearly illustrated by
glucagon and VIP as by insulin: whereas all other
mammals have a glucagon of 29 amino acids, the
guinea-pig molecule is 40 amino acids long. Similarly, the VIP sequences of all other mammals are
identical but guinea-pig VIP differs in 4 of the
28 amino acids [55]. The VIP of the chicken also
differs from the typical mammalian sequence at
four positions and those of the cod Gadus morrhua and the shark Scyliorhinus canicula differ at
eight positions [52]. GIP is not quite as highly
conserved, with the human sequence differing in
2 and 4 of 42 amino acids from the porcine and
bovine sequences, respectively [214]. Secretin is a
8.5 Peptides Regulating Blood Pressure
301
peptide of 27 residues that stimulates pancreas
secretion. The rat secretin gene shows homology
only to the other genes of this hormone family in
the exons encoding the bioactive peptide, and the
only translated product is secretin, whereas the
genes for pro-glucagon and pro-VIP each produce
several different bioactive peptides [88, 107].
8.4.4 The Family of Pancreas Polypeptides
The pancreas polypeptide (PP) of the chicken,
discovered in 1975, is a C-terminal amidated peptide of 36 amino acids that functions as an antagonist of glucagon, inhibiting lipolysis in the fat
cells. PP belongs to a family of polypeptides
including peptide YY from the gut wall (PYY)
and from the brain NPY, with which it shows
50-70 % similarity [202, 216]; also included is
peptide YG from the pancreas of the angler fish
Lophius americanus (aPY). The PP-producing
cells are a specific type of endocrine pancreatic
cell distinct from the glucagon-producing A
cells, the insulin-producing B cells and the
somatostatin-producing D cells. The human,
sheep and cat PP precursor includes a C-terminal
20-residue peptide that is absent in the rat and the
mouse. The guinea-pig, whose insulin and glucagon differ markedly from those of other mammals, produced a PP precursor with 89 % agreement to the human molecule in the hormone
region but with only 40 % similarity in the icosapeptide part [15,244]. The aPY precursor is
identical in structure to that of PP. The 64 % similarity of the active peptide of aPY with PP and
NPY is much greater than the agreement between
the remaining regions; this is comparable with the
higher rate of evolution of the insulin C peptide
compared with the A and B chains [7]. PPs have
been reported from many vertebrate species and
have 9 out of 36 invariant residues [125, 171]. PPlike substances have also been detected in annelids and insects.
8.5 Peptides Regulating Blood Pressure
The juxtaglomerular cells situated in the kidney
glomeruli release renin in response to a decrease
in blood pressure or to sodium deficiency. Renins
are found in several forms; as well as in the kidneys, they are produced in the salivary glands and
in the female genital tract. They are all glycoproteins of about 40 kDa, made up of two chains