237PLC inhibition, stimulated by PST, probably mediating a negative feed-back of PST
signaling (Sanchez-Margalet and Goberna 1994b).
Using different approaches (GTP-γ-S binding, GTP-azido photolabeling, and
GTPase activity), in rat liver membranes, our group has demonstrated that a pertussis
toxin-insensitive stimulation of PLC by PST, is mediated by the activation of a G
protein of the Gαq/11 family, while the PST activated pertussis toxin-insensitive G pro-
tein is a part of the Gα1,2 family (Sanchez-Margalet 1999 ; Santos-Alvarez and Sanchez-
Margalet 1998 ). Therefore, the activation of PLC by PST is mediated by Gα 11 rather
than Gαq, and more precisely, PLC-β3 is the isoform activated in rat liver membranes
by PST (see the Fig. 2 ) (Santos-Alvarez and Sanchez-Margalet 1998 ).
In recent CGA knock-out studies, it has been found that the lack of CGA expres-
sion leads to a decreased hepatic gluconeogenesis, a diminished glycaemia and an
enhanced insulin sensitivity, despite of a high levels of corticosterone, and catechol-
amines, which may cause the observed hypertension. The increase in catechol-
amines could be a consequence of the loss of the CGA-derived peptide catestatin.
The interpretation of these data is that PST may decrease insulin sensitivity, and the
lack of PST may help to maintain euglycemia, since the inhibitory effect of PST on
IRS1/2-PI3K-AKT signaling (reached through NOS and cPKC inactivation) would
be not present, and therefore, insulin would generate an increased inhibition of
hepatic gluconeogenesis. Thus, in normal conditions PST should enhance the
Fig. 2 Model of PST mechanism of action in hepatocyte. PST binds to its putative receptor at the
plasma membrane, activating signaling through a Gα 11 protein. The activation of a Gα 11 stimulates
PLC-β3 increasing the production of IP3 and DAG, and finally, the activated PKC and calcium
dependent kinases mediate the metabolic effects. PKC phosphorylates the insulin receptor inhibit-
ing its activity and counterregulating insulin action. Gαi1,2 appears to mediate the production of
cGMP inhibiting PLC activity to downregulate PST signaling
Action and Mechanisms of Action of the Chromogranin A Derived Peptide Pancreastatin