Figure 5. Proposed model for CaSR-mediated increase in fetal lung fluid secretion.

In both the mouse and human activation of the CaSR via the calcimimetic NPS R-568 leads to an increase in cytosolic Ca²⁺ through activation of the PI-PLC pathway and release of Ca²⁺ from intracellular stores. This rise in cytosolic calcium leads to an increase in intracellular cAMP level via a Ca²⁺-stimulated adenylate cyclase (AC1), and in turn activation of the cAMP-dependent enzyme protein kinase A (PKA). Phosphorylation of the CFTR’s regulatory ‘R’-domain by PKA allows opening of the channel and conductance of Cl⁻ ions through the channel. A similar pathway also appears to be in place in response to fetal hypercalcemia in the human fetal lung, however this is not the case in the mouse where as yet unknown pathway, not involving an apical CFTR channel, appears to induce this increase in fluid secretion.