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1Division of Pediatric Nephrology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York; and 2Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Submitted 6 February 2007 ; accepted in final form 25 March 2007
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 1) blocked by iberiotoxin, an inhibitor of BK but not SK channels, and 2) 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–1·mm–1) 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. Am J Physiol Renal Physiol 291: F663–F669, 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. Am J Physiol Renal Physiol 291: F663–F669, 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.
maxi-K channel; BK channel; SK channel; mechanoregulation; ENaC
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