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et al. 2010 ). High affinity PST receptors have been characterized by our group and
their signal transduction in liver and adipose tissue, so, the basis for the molecular
mechanisms of the PST effects observed in glucose and lipid metabolism has been
elucidated. Therefore it’s foreseeable that PST displays its endocrine actions in
stressful conditions when circulating PST levels are high enough to interact with
specific receptors in target cells.
The mechanisms by which PST controls stress metabolism seems to be the inhib-
itory crosstalk with insulin receptor pathway. In this way, in CGA knockout mouse,
the inhibition of IRS-1/2-PI3K-Akt signaling pathway by PST has been confirmed,
which is consistent with previous in vitro studies with hepatocytes and adipocytes
(Sanchez-Margalet et al. 2000 ; Gonzalez-Yanes et al. 1999 ). Nevertheless, despite
these findings, some questions about PST signaling are still awaiting for further
elucidation. Although active PST receptors were purified from rat liver membranes
and shown association with a Gαq / 11 protein (Santos-Alvarez and Sanchez-Margalet
2000 ) the complete characterization and sequencing of such receptor was not pos-
sible. Even so, PST physiological actions could have behand them the Gq-PLC-
calcium-PKC and protein kinase- Ca2+/ NO mediated signaling pathway activation
(Gayen et al. 2009 ; Santos-Alvarez and Sanchez-Margalet 1999 ; Sanchez-Margalet
and Goberna 1994a, b; Sanchez-Margalet et al. 1994a, b).
In this physiological stress context, a novel PST target has been discovered
recently in liver tissue, the adaptive UPR chaperone GRP78 also known as “Glucose-
Regulated Protein”. In summary, GRP78 may function in stress conditions as bind-
ing and degrading undesirable proteins. PST was found not only to bind GRP78 (in
pH-dependent manner), but also to inhibit its ATPase enzymatic activity, resulting
in enhanced G6P-ase expression and reduced glucose uptake (Biswas et al. 2014 ).
In this way it seems possible that PST could regulate the energy availability, in a
global manner, through very different mechanisms, such as insulin signaling antag-
onism, as well as regulation of protein folding, and other remaining unknown pos-
sible ways.
7 PST Natural Occurring Variants and Its Implications
Finally, recent studies of the Indian population revealed different biological potency
among natural PST peptide variants. Thus, two potent PST naturally occurring vari-
ants have been discovered: a more frequent (G297S) and an unusual one (PST287K),
with more potent activity than WT-PST. This is not surprising, since both variants
differ in the amino acid content of the C-terminus fragment, the responsible of PST
biological activity. Thus, both variants have been shown to have higher activity than
WT-PST in a variety of biological effects: decreased insulin stimulated glucose
uptake, increased intracellular NO and Ca2+ levels, and enhanced gluconeogenesis
enzymes expression. This enlarged activity keeps close relationship with a more
ordered secondary structure of the resultant peptide, which results in a higher
α-helicoidal content. In this way, the quantity of alpha-helices structures is higher in
N.E. Evtikhova et al.