TY  - JOUR
AU  - Comini, Maddalena
AU  - Sierra-Marquez, Juan
AU  - Guzman, Gustavo
AU  - Franzen, Arne
AU  - Willuweit, Antje
AU  - Katona, Istvan
AU  - Hidalgo, Patricia
AU  - Fahlke, Christoph
AU  - Guzman, Raul E.
TI  - CLC Anion/Proton Exchangers Regulate Secretory Vesicle Filling and Granule Exocytosis in Chromaffin Cells
JO  - The journal of neuroscience
VL  - 42
IS  - 15
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.
M1  - FZJ-2022-03681
SP  - 3080-3095
PY  - 2022
AB  - ClC-3, ClC-4, and ClC-5 are electrogenic chloride/proton exchangers that can be found in endosomal compartments of mammalian cells. Although the association with genetic diseases and the severe phenotype of knock-out animals illustrate their physiological importance, the cellular functions of these proteins have remained insufficiently understood. We here study the role of two Clcn3 splice variants, ClC-3b and ClC-3c, in granular exocytosis and catecholamine accumulation of adrenal chromaffin cells using a combination of high-resolution capacitance measurements, amperometry, protein expression/gene knock out/down, rescue experiments, and confocal microscopy. We demonstrate that ClC-3c resides in immature as well as in mature secretory granules, where it regulates catecholamine accumulation and contributes to the establishment of the readily releasable pool of secretory vesicles. The lysosomal splice variant ClC-3b contributes to vesicle priming only with low efficiency and leaves the vesicular catecholamine content unaltered. The related Cl−/H+ antiporter ClC-5 undergoes age-dependent downregulation in wild-type conditions. Its upregulation in Clcn3−/− cells partially rescues the exocytotic mutant defect. Our study demonstrates how different CLC transporters with similar transport functions, but distinct localizations can contribute to vesicle functions in the regulated secretory pathway of granule secretion in chromaffin cells.
LB  - PUB:(DE-HGF)16
C6  - 35241492
UR  - <Go to ISI:>//WOS:000789016600003
DO  - DOI:10.1523/JNEUROSCI.2439-21.2022
UR  - https://juser.fz-juelich.de/record/910204
ER  -