Caveolin‐1 modulates the activity of the volume‐regulated chloride channel

Abstract

Caveolae are Ù-shaped invaginations of the plasma membrane with a diameter of 50-100 nm that are present in many different cell types (Anderson, 1998). Caveolae form discrete lipid microdomains within the plasma membrane due to the preferential packing of sphingolipids and cholesterol. The principal protein component of caveolae is caveolin, a 21-24 kDa membrane protein that inserts into the caveolar membrane via an intramembrane hairpin loop. Four different isoforms encoded by three genes have been described: caveolin_1á, _1â, _2 and _3 (Parton, 1996). Caveolins form homo-and hetero-oligomeric complexes (Song et al. 1997) that bind to cholesterol and sphingolipids, which seems to be an important step in the formation of caveolae (Li et al. 1996). Heterologous expression of caveolin_1 in lymphocytes or CaCo_2 cells that lack both caveolin_1 and morphological caveolae induces the appearance of caveolae in the plasma membrane (Fra et al. 1995;Mirre et al. 1996;Vogel et al. 1998). It has recently emerged that caveolae form specialised membrane compartments involved in signal transduction with caveolin_1 forming a molecular scaffold onto which signalling proteins such as the endothelial NO synthase, the c-src protein tyrosine kinase or small GTPases such as Ras and Rho are assembled in their inactive configuration (Okamoto et al. 1998).

Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation

“…This activity was blocked by the addition of RU486, indicating that upregulation of caveolin-1 by MPA is mediated by the classical PR. Similar experiments were conducted in human breast cancer T47D cells which do not express caveolin-1, as shown by others (Trouet et al, 1999) and by our own experiments (data not shown). On T47D cells, progesterone has biphasic effects: stimulating growth first (0-24 h) and then inhibiting it (24-48 h) (Lange et al, 1999).…”

Chloride intracellular channel protein CLIC4 (p64H1) binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms

“…The association of previously separate proteins that might then be able to activate ion channels could also be important. Consistent with this novel ' occluded anion channel ' hypothesis are the observations that caveolins modulate volume-regulated anion channel activity [54] and that caveolae cluster centrally in cells exposed to hyperosmotic medium, provided that the actin and microtubule cytoskeletons both remain intact [55].…”

Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin

“…This, on the other hand, seems in contrast to the recent proposal that VRAC activation is dependent on the integrity of caveolae (63), and that caveolin-1 may increase VRAC availability in the plasma membrane and/or be involved in the signaling events leading to VRAC activation (64).…”

“…RhoA and Rho kinase exhibit activity-dependent translocation to caveolae (62,65), suggesting a role for cholesterol depletion-induced changes in caveolae organization. Interestingly, caveolae are also sensitive to cell volume perturbations (46), and have been implicated in VRAC regulation (63,64). On the other hand, preliminary studies revealed no detectable changes in caveolin-1 distribution in cholesterol-depleted ELA cells (S. F. Pedersen, T. Kjaer Klausen, and E. K. Hoffmann, unpublished observations).…”