FIGURE 2.

Schematic drawing showing the intercellular communication model regulating the luminal microenvironment in the epididymis. The model includes several physiological processes: 1) anion secretion (e.g., HCO₃ ⁻) via apically located CFTR (and/or other anion channels, such as TMEM16A) provides an ionic gradient which drives fluid transport through water channels, e.g., aquaporin 9 (AQP9); 2) proton-pump V-ATPase acidifies the luminal content and promotes HCO₃ ⁻ hydrolysis for water and CO₂ absorption, an essential acidification process required for maintaining sperm in a quiescent state and to prevent premature activation. The acidification process is mediated by either constitutively by recycling of the V-ATPases which are abundantly expressed in clear cells, or by the stimulation of luminal factors, such as ATP generated by principal cells or nitric oxide (NO) from the basal cells upon stimulation by the angiotensin receptor type 2 (AGTR2); and 3) Ca²⁺ reabsorption through either the epithelial Ca²⁺ channel TRPV6 and Ca²⁺-dependent Cl⁻-channel TMEM16A electrical coupler or via a process facilitated by GGCX-mediated carboxylation-dependent activation of MGP for Ca²⁺ chelation and simultaneous protein aggregation, such as lipocalin 2 (LCN2).