Ca2+ Signaling in Exocrine Cells

Abstract

Calcium (Ca²⁺) and cyclic AMP (cAMP) signaling cross talk and synergize to stimulate the cardinal functions of exocrine cells, regulated exocytosis, and fluid and electrolyte secretion. This physiological process requires the organization of the two signaling pathways into complexes at defined cellular domains and close placement. Such domains are formed by membrane contact sites (MCS). This review discusses the basic properties of Ca²⁺ signaling in exocrine cells, the role of MCS in the organization of cell signaling and in cross talk and synergism between the Ca²⁺ and cAMP signaling pathways and, finally, the mechanism by which the Ca²⁺ and cAMP pathways synergize to stimulate epithelial fluid and electrolyte secretion.

Figure 1.

Receptor-specific initiation site and propagation pattern of Ca²⁺ waves. Cells were sequentially stimulated with 5 μm carbachol and 0.25 nm cholecystokinin (CCK), as indicated in the traces in the upper panel. (A) Initiation site and pattern of the Ca²⁺ wave evoked by activation of the M3 and CCK receptors in the same cell. (B,C) Additional examples of the different Ca²⁺ wave initiation sites evoked by carbachol (white arrowhead) and CCK (magenta arrowhead) stimulation in the same cells. AM, Apical membrane; BM, basal membrane. (From Shin et al. 2001; adapted, with permission, from the American Society for Biochemistry and Molecular Biology © 2001.)

Figure 2.

Molecular mechanism of synergism in cyclic AMP (cAMP) and Ca²⁺ signaling in epithelial fluid and HCO₃⁻ secretion. In the resting state, IRBIT recruits the WNK/SPAK and CaMKII kinases to the transporters to phosphorylate NBCe1-B autoinhibitory domain, Slc26a6 and CFTR to sequester most of them in intracellular compartments. Al low cytoplasmic IP₃, most IRBIT is bound to the IP₃ receptors, which in secretory glands are expressed at high levels at the apical pole. When the cells are stimulated with a combination of physiological concentrations of IP₃ and cAMP-generating agonists, PKA phosphorylates the IP₃Rs to facilitate the IP₃-mediated release of IRBIT from the IP₃Rs. IRBIT recruits protein phosphatase 1 (PP1) and calcineurin (CaN) to the transporters to dephosphorylate them and fuse the intracellular transporters pool with the PM. IRBIT remains bound to the transporters to relieve their constitutive inhibition and expose their intracellular Cl⁻ regulatory sites. The IRBIT-activated transporters mediate fluid and electrolyte secretion by CFTR-expressing epithelia.