Lerias, Joana and Pinto, Madalena and Benedetto, Roberta and Schreiber, Rainer and Amaral, Margarida and Aureli, Massimo and Kunzelmann, Karl (2018) Compartmentalized crosstalk of CFTR and TMEM16A (ANO1) through EPAC1 and ADCY1. CELLULAR SIGNALLING, 44. pp. 10-19. ISSN 0898-6568, 1873-3913
Full text not available from this repository. (Request a copy)Abstract
Airway epithelial cells express both Ca2+ activated TMEM16A/ANO1 and cAMP activated CFTR anion channels. Previous work suggested a significant crosstalk of intracellular Ca2+ and cAMP signaling pathways, leading to activation of both chloride channels. We demonstrate that in airway epithelial cells, stimulation of purinergic or muscarinic G-protein coupled receptors (GPCRs) activates TMEM16A and CFTR. Additional expression of G(q/11) and phospholipase C coupled GPCRs strongly enhanced the crosstalk between Ca2+ - and cAMP-dependent signaling. Knockdown of endogenous GRCRs attenuated crosstalk and functional coupling between TMEM16A and CFTR. The number of receptors did not affect expression or membrane localization of TMEM16A or CFTR, but controlled assembly of the local signalosome. GPCRs translocate Ca2+-sensitive adenylate cyclase type 1 (ADCY1) and exchange protein directly activated by cAMP (EPAC1) to particular plasma membrane domains containing GPCRs, CFTR and TMEM16A, thereby producing compartmentalized Ca2+ and CAMP signals and significant crosstalk. While biosynthesis and membrane trafficking of CFTR requires a functional Golgi apparatus, maturation and membrane trafficking of TMEM16A may occur independent of the Golgi. Because Ca2+ activated TMEM16A currents are only transient, continuous Cl- secretion by airway epithelial cells requires CFTR. The present data also explain why receptor-dependent activation of TMEM16A is more efficient than direct stimulation by Ca2+.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSMEMBRANE CONDUCTANCE REGULATOR; CHLORIDE CHANNEL; LIPID RAFTS; ACTIVATION; MEMBRANE; ANOCTAMINS; EXPRESSION; CELLS; CFTR; TMEM16A; Anoctamin 1; Ca2+ activated Cl- channel; cAMP; Ca2+ sensitive adenylate cyclase 1; ADCY1; Exchange protein directly activated by cAMP; EPAC1 |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2020 09:08 |
| Last Modified: | 19 Mar 2020 09:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14864 |
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