Abstract

Caveolae, 50-75nm invaginations of the plasma membrane (PM), were
originally described by the late Nobel Prize-winning cell biologist George Palade
(1). They are a subset of membrane lipid rafts (MLR), microdomains of the
plasmalemma highly enriched in cholesterol and glycosphingolipids. Caveolins
(Cav-1, Cav-2 and Cav-3) are scaffolding and cholesterol binding proteins that
localise to the inner leaflet of the PM within caveolae and insert via palmitoylated
cysteine residues. Caveolins (Cavs) interact with and bind many signalling
transduction proteins, such as G-protein-coupled receptor (GPCR) signalling
components, and also serve to modulate the cytoskeleton via tethering to actin
and/or microtubules. By acting within the MLR domain, Cavs drive pro-survival
pathways (p-Src, p-Akt, p-ERK), leading to protective phenotypes. I have shown
Cav-1KO mice have a neurodegenerative phenotype, whilst also demonstrating
viral driven increased expression of Cav-1 enhances dendritic growth in neurons.
Cav-3 can increase protective or anti-apoptotic signalling events in the heart.
Cav-3 overexpressing mice have increased morphological caveolae quantitated
with my TEM images and have enhanced protection from injury. Cav-3KO mice,
with disrupted mitochondrial and sarcomeric ultrastructure analysed by me, are at
significant risk of cardiomyopathies, revealing a critical role for Cavs in protection.
Using multiple and complementary techniques, new cellular functions, beyond
the previously described role as protein scaffolds in signalling networks, have
been uncovered for Cavs isoforms. I have discovered increased numbers of
caveolae following virus-mediated transfection, preconditioning (protective)
protocols and some pathological states. In contrast, I have found decreased
caveolae and other pathologies associated with reduced Cavs expression.
Localisation of Cavs in non-canonical cellular domains, such as mitochondria and
cytoskeletal fractions, established by my LM, TEM and cell fractionation
analyses, have led to the hypothesis that Cavs are critical cellular regulators. And
as such, represent an attractive pharmacological target for diseases with diverse
aetiologies, including cardiomyopathies, neurodegenerative diseases, diabetes
and inflammation.