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1 Department of Pediatrics, Box 1664, Mount Sinai School of Medicine, New York, New York, United States; Pediatrics, Mount Sinai School of Medicine, New York, New York, United States
2 Department of Pediatrics, Box 1664, Mount Sinai School of Medicine, New York, New York, United States
3 Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: lisa.satlin{at}mssm.edu.
Apical low-conductance SK and high-conductance Ca2+-activated BK channels are present in distal nephron, including the cortical collecting duct (CCD). Flow-stimulated net K secretion (JK) in the CCD is (i) blocked by iberiotoxin, an inhibitor of BK but not SK channels, and (ii) associated with an increase in [Ca2+]i, leading us to conclude that BK channels mediate flow-stimulated JK. To examine the Ca2+-dependence and sources of Ca2+ contributing to flow-stimulated JK, JK and net Na absorption (JNa) were measured at slow (~1) and fast (~5 nl/min.mm) flow rates in rabbit CCDs microperfused in the absence of luminal Ca2+ or after pretreatment with BAPTA-AM to chelate intracellular Ca2+, 2-aminoethoxydiphenyl borate (2-APB) to inhibit the inositol 1,4,5-trisphosphate (IP3) receptor, or thapsigargin to deplete internal stores. These treatments, which do not affect flow-stimulated JNa (Morimoto et al, AJP 291:F663-9, 2006), inhibited flow-stimulated JK. Increases in [Ca2+]i stimulate exocytosis. To test whether flow induces exocytic insertion of preformed BK channels into the apical membrane, CCDs were pretreated with 10 µM colchicine (COL) to disrupt microtubule function or 5 µg/ml brefeldin-A (BFA) to inhibit delivery of channels from the intracellular pool to the plasma membrane. Both agents inhibited flow-stimulated JK but not JNa (Morimoto et al, AJP 291:F663-9, 2006), although COL but not BFA also blocked the flow-induced [Ca2+]i transient. We thus speculate that BK channel-mediated flow-stimulated JK requires an increase in [Ca2+]i due in part to luminal Ca2+ entry and ER Ca2+ release, microtubule integrity, and exocytic insertion of preformed channels into the apical membrane.
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