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through the involvement of Akt dependent eNOS phosphorylation (Shaul et al.
2002 ). In line with this scenario, experiments on papillary muscles and BAE-1 cells
exposed to rCgA1-64, and treated with the PI3K inhibitor Wortmannin, indicate that
the NO release induced by the rat peptide depends on PI3K activation (Cerra et al.
2008 ). Interestingly, Maniatis et al. ( 2006 ), proposed that eNOS may be activated in
a calcium-independent manner by involving a caveolae-mediated endocytosis elic-
ited by the albumin-binding protein gp60 and activation of downstream Src, Akt and
PI3K pathways. It has been hypothesized that VSs interacts with caveolar domain
(see for references, Tota et al. 2007 ), and that endothelial cells internalize CgA1-78
(Ferrero et al. 2004 ). Therefore, a similar mechanism may explain the VS-1-
dependent NOS activation in BAE-1 cells. However, this remains an open field for
investigations (Fig. 3 ).
In the search of possible mechanisms of interaction between VSs peptides and
the cell membrane, and in the absence of either a conventional receptor or an action
Fig. 2 The sigmoid concentration-response curves of Isoprenaline (ISO)-mediated stimulation
(10-10-10-6 M) alone (a–c) and of ISO plus a single concentration of human VS1 (STA-CGA1-78)
at 11, 33, and 65 nM (a) and of ISO plus a single concentration of propranolol at 30 nM, 0.3 μM,
1 μM and 3 μM (b) and ISO plus a single concentration of Catestatin (WT-Cst) at 11, 33, and
110 nM (c). Concentration is expressed as a percentage [baseline = 0%, peak constriction by ISO
and ISO plus VS1 or propranolol or CST = 100%] (Modified by Tota et al. 2008 and Angelone
et al. 2008 )
T. Angelone et al.