cAMP and Ca²⁺ signaling in secretory epithelia: crosstalk and synergism

Abstract

The Ca(2+) and cAMP/PKA pathways are the primary signaling systems in secretory epithelia that control virtually all secretory gland functions. Interaction and crosstalk in Ca(2+) and cAMP signaling occur at multiple levels to control and tune the activity of each other. Physiologically, Ca(2+) and cAMP signaling operate at 5-10% of maximal strength, but synergize to generate the maximal response. Although synergistic action of the Ca(2+) and cAMP signaling is the common mode of signaling and has been known for many years, we know very little of the molecular mechanism and mediators of the synergism. In this review, we discuss crosstalk between the Ca(2+) and cAMP signaling and the function of IRBIT (IP3 receptors binding protein release with IP3) as a third messenger that mediates the synergistic action of the Ca(2+) and cAMP signaling.

Keywords: Calcium signaling; Duct epithelia; IRBIT; Synergism.

Fig. 1

Interactions in the Ca²⁺ and cAMP signaling pathways

Fig. 2. IRBIT mediates the synergistic activation of native slc26a6 and CFTR by the Ca²⁺ and cAMP signaling pathways

Panel (a): Cl⁻/HCO₃⁻ exchange activity was estimated from the change in intracellular pH (pH_in) in response to removal and re-addition of external Cl⁻. pH_in was measured in isolated duct fragments from the submandibular glands of wild-type (green and blue traces and columns) and IRBIT^−/− mice (red trace and column). Panel (b): Ductal CFTR activity was measured as a forskolin-stimulated CFTR_inh172- inhibited Cl⁻/NO₃⁻ exchange in wild-type (red and blue traces and columns) and IRBIT^−/− (green and magenta traces and columns) ducts. The results were taken from [58].

Fig. 3. PKA-mediated phosphorylation of IP₃R1 facilitates dissociation of IP₃Rs-IRBIT complexes by IP₃

Panel (a) show that IRBIT and IP₃R1 expressed in intact HeLa cells interact and the complexes are dissociated by maximal stimulation of the Gq-coupled P2Y2 receptors with 10 μM ATP or by the concomitant stimulation with low concentrations of ATP and forskolin, but not by stimulation with low concentrations of either ATP or forskolin. Panel (b) shows that the IP₃Rs mutants resists (IP₃R1(AA)) and facilitates (IP₃R1(EE)) dissociation of the IRBIT-IP₃R1 complexes. Panels (c, d) show the expression of the mutant IP₃R1(AA) in the duct eliminates the synergistic activation of ductal Cl⁻/HCO₃⁻ exchange (c) and CFTR (d) by low concentrations of carbachol and forskolin. The results were taken from [58].

Fig. 4. IRBIT mediates the synergistic activation of ductal fluid secretion by the PKA and Ca²⁺ signaling pathways

Panels (a, b) show that IRBIT is required for synergistic activation of ductal fluid secretion. Fluid secretion in pancreatic ducts from wild-type (a) and IRBIT^−/− (b) mice was measured in sealed ducts in HCO₃⁻-buffered media and stimulated with 5 or 0.1μM forskolin, 1μM carbachol or both 0.1μM forskolin and 1μM carbachol. The results were taken from [58].