Activation of the Ae4 (Slc4a9) cation-driven Cl−/HCO3− exchanger by the cAMP-dependent protein kinase in salivary gland acinar cells

Ae4 transporters are critical for Cl− uptake across the basolateral membrane of acinar cells in the submandibular gland (SMG). Although required for fluid secretion, little is known about the physiological regulation of Ae4. To investigate whether Ae4 is regulated by the cAMP-dependent signaling pat...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2021-12, Vol.321 (6), p.G628-G638
Main Authors: Peña-Münzenmayer, Gaspar, Kondo, Yusuke, Salinas, Constanza, Sarmiento, José, Brauchi, Sebastián, Catalán, Marcelo A
Format: Article
Language:English
Subjects:
Acinar cells
Adrenergic receptors
Alanine
Cyclic AMP
Homology
Kinases
Mutants
Phosphorylation
Protein kinase A
Salivary gland
Sequence analysis
Signal transduction
Submandibular gland
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Summary:Ae4 transporters are critical for Cl− uptake across the basolateral membrane of acinar cells in the submandibular gland (SMG). Although required for fluid secretion, little is known about the physiological regulation of Ae4. To investigate whether Ae4 is regulated by the cAMP-dependent signaling pathway, we measured Cl−/HCO3− exchanger activity in SMG acinar cells from Ae2−/− mice, which only express Ae4, and found that the Ae4-mediated activity was increased in response to β-adrenergic receptor stimulation. Moreover, pretreatment with H89, an inhibitor of the cAMP-activated kinase (PKA), prevented the stimulation of Ae4 exchangers. We then expressed Ae4 in CHO-K1 cells and found that the Ae4-mediated activity was increased when Ae4 is coexpressed with the catalytic subunit of PKA (PKAc), which is constitutively active. Ae4 sequence analysis showed two potential PKA phosphorylation serine residues located at the intracellular NH2-terminal domain according to a homology model of Ae4. NH2-terminal domain Ser residues were mutated to alanine (S173A and S273A, respectively), where the Cl−/HCO3− exchanger activity displayed by the mutant S173A was not activated by PKA. Conversely, S273A mutant kept the PKA dependency. Together, we conclude that Ae4 is stimulated by PKA in SMG acinar cells by a mechanism that probably depends on the phosphorylation of S173.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00145.2021