FIGURE 1.

Principal defects in Ca²⁺ signaling associated with defective CFTR channel. Schematic representation of intracellular Ca²⁺ signaling in airway cells. The cellular Ca²⁺ homeostasis is regulated by systems of Ca²⁺-entry and Ca²⁺-efflux located in plasma membrane and organelles. In the inset are reported the principal molecular systems involved in the abnormal intracellular Ca²⁺ signaling associated with defective CFTR channel, where the their dysfunction contributes to physiopathology of CF lung disease: I) increased PLC activity, due to GPCR-dependent overstimulation; II) increased TRP-dependent Ca²⁺-entry, due to enhanced functional activity and/or expression; III) increased Orai insertion with consequent augments in Ca²⁺-influx; IV) increased SERCA activity; V) increased MCU activity; and VI) reduced Ca²⁺-efflux, due to altered PMCA activity. ATP, adenosine triphosphate; Ca²⁺, calcium; CFTR, cystic fibrosis transmembrane conductance regulator; Cl-, chloride; DAG, diacylglycerol; ER, endoplasmic reticulum; GPCR, G protein coupled receptor; GPD, guanosine diphosphate; GRP75, glucose-related protein 75; IP3, inositol 1,4,5-triphosphate; IP3Rs; inositol trisphosphate receptors; MCU, mitochondrial calcium uniporter; NCX, sodium-calcium exchanger; Orai, calcium release activated calcium channel; PLC, phospholipase C; PM, plasma membrane; PMCA, PM-resident Ca²⁺-ATPase; SERCA, ER-resident Ca²⁺-ATPase; STIM1; stromal interaction molecule 1; TRPC, transient receptor potential (TRP) channels; VDAC1, voltage-dependent anion-selective channel 1.