Fig. 10. Model for biphasic modulation of cholesterol in bicarbonate-stimulated sperm cells. (A) In the absence of high levels of bicarbonate (i.e. in epididymal or seminal fluids) phospholipid scrambling is blocked. Cholesterol has a wide-spread lateral localization in the sperm head plasma membrane; caveolin-1-mediated raft formation does not take place. (B) In the presence of high levels of bicarbonate a soluble adenylate cyclase is activated by bicarbonate (entry by the bicarbonate chloride exchanger), which triggers production of cAMP and activates protein kinase A (Cheng et al., 2000). This pathway leads to the activation of phospholipid scrambling in the apical plasma membrane of the sperm head (Gadella and Harrison 2000; Gadella et al., 1999b) via a yet unclear pathway. This apical scrambling coincides with the concentration of cholesterol in this area (M540 correlated with both responses). The preliminary finding that caveolin-1 is present in sperm cells makes it possible that the scrambling surface area (concentration of cholesterol) is forming a membrane raft. Note that phospholipid scrambling-induced membrane blebbing may be compensated with the caveolin-1-induced membrane invagination. If a membrane raft is formed, a scavenger receptor (SRB-1) may be able to transport cholesterol out of the apical plasma membrane of the sperm head (Fielding and Fielding, 2000). (C) This will only lead to a decrease of cellular cholesterol if an acceptor of cholesterol (e.g. BSA) is present.