Membrane-specific Regulation of Cl− Channels by Purinergic Receptors in Rat Submandibular Gland Acinar and Duct Cells

Abstract

Measurement of [Cl] i , BzATP in both SMG cell types largely activated the Ca 2؉ -independent, glibenclamide-sensitive Cl ؊ current, whereas UTP activated only the Ca 2؉ -dependent Cl ؊ current. We interpret this to suggest that BzATP and UTP largely activate Cl ؊ channels residing in the membrane expressing the receptor for the active nucleotide. The present studies reveal a potentially new mechanism for transcellular Cl ؊ transport in a CFTR-expressing tissue, the SMG. Coordinated action of the P 2 z (luminal) and P 2 u (basolateral) receptors can mediate part of the transcellular Cl ؊ transport by acinar and duct cells to determine the final electrolyte composition of salivary fluid.

Purinergic Stimulation Induces Ca2+-dependent Activation of Na+-K+-2Cl- Cotransporter in Human Nasal Epithelia

“…Previously, we showed that P2R signals evoke the membrane-specific activation of ion transporters in polarized epithelial tissues (27,28). In the present study, the stimulatory effects of luminal ATP on NKCC were partially inhibited by the blockade of luminal Cl Ϫ channels (Fig.…”

Tmem16A Encodes the Ca2+-activated Cl− Channel in Mouse Submandibular Salivary Gland Acinar Cells

“…Previous reports demonstrate that members of the TMEM16 (4 -7) and BEST (8,(11)(12)(13) gene families encode Ca 2ϩ -activated Cl Ϫ channels with properties much like those found in native tissues (1,(15)(16)(17)(18). TMEM16A was previously detected in a proteomics screen of exosomal proteins isolated from human parotid saliva (32) and in the apical membrane of mouse salivary acinar cells (6), whereas mouse salivary gland acinar cells express transcripts for Best2 (9).…”

“…-dependent Cl Ϫ channels are fundamental to the function of numerous organ systems such as membrane potential regulation in excitable cells (52,53) and fluid secretion by exocrine gland acinar cells (15)(16)(17)(18). Nevertheless, unequivocal molecular identification of the CaCC in these various cell types is generally lacking.…”

“…Instead, the Cl Ϫ current in these cells displayed two components. The first was a current with biophysical and pharmacological properties like VRAC, a cell volume-activated anion current (40,41) that is very different from the outward rectifying, slowly developing CaCC current found in salivary gland acinar cells (15,18). The second Cl Ϫ current was activated at negative potentials in a time-dependent and NFA-insensitive manner, reminiscent of the inward rectifying Cl Ϫ current in mouse submandibular duct cells that is inhibited by cadmium and is absent in ClC-2 null mice (37).…”

“…Both bestrophin and TMEM16 channels have been shown to generate Ca 2ϩ -activated Cl Ϫ currents in vitro that are dependent on physiological intracellular Ca 2ϩ concentrations (4 -6, 8 -10). TMEM16 and BEST Ca 2ϩ -activated Cl Ϫ channels (4 -6, 8, 11-14) share many of the functional and pharmacological properties of the CaCC expressed in native secretory cells (15)(16)(17)(18), unlike the other putative Ca 2ϩ -activated Cl Ϫ channels, i.e. CLCA, CLC3, and TWEETY (19 -22).…”