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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Evidence for KCNQ1 K⁺ channel expression in rat zymogen granule membranes and involvement in cholecystokinin-induced pancreatic acinar secretion

¹Department of Physiology and Pathophysiology, University of Witten/Herdecke, Witten, Germany; and ²Institute of Anatomy and Cell Biology, Department of Molecular Embryology, University of Freiburg, Freiburg, Germany

Submitted 17 October 2007 ; accepted in final form 18 January 2008

Secretion of enzymes and fluid induced by Ca²⁺ in pancreatic acini is not completely understood and may involve activation of ion conductive pathways in zymogen granule (ZG) membranes. We hypothesized that a chromanol 293B-sensitive K⁺ conductance carried by a KCNQ1 protein is expressed in ZG membranes (ZGM). In suspensions of rat pancreatic ZG, ion flux was determined by ionophore-induced osmotic lysis of ZG suspended in isotonic salts. The KCNQ1 blocker 293B selectively blocked K⁺ permeability (IC₅₀ of 10 µM). After incorporation of ZGM into planar bilayer membranes, cation channels were detected in 645/150 mM potassium gluconate cis/trans solutions. Channels had linear current-voltage relationships, a reversal potential (E_rev) of –20.9 ± 0.9 mV, and a single-channel K⁺ conductance (g_K) of 265.8 ± 44.0 pS (n = 39). Replacement of cis 500 mM K⁺ by 500 mM Na⁺ shifted E_rev to –2.4 ± 3.6 mV (n = 3), indicating K⁺ selectivity. Single-channel analysis identified several K⁺ channel groups with distinct channel behaviors. K⁺ channels with a g_K of 651.8 ± 88.0 pS, E_rev of –22.9 ± 2.2 mV, and open probability (P_open) of 0.43 ± 0.06 at 0 mV (n = 6) and channels with a g_K of 155.0 ± 11.4 pS, E_rev of –18.3 ± 1.8 mV, and P_open of 0.80 ± 0.03 at 0 mV (n = 3) were inhibited by 100 µM 293B or by the more selective inhibitor HMR-1556 but not by the maxi-Ca²⁺-activated K⁺ channel (BK channel) inhibitor charybdotoxin (5 nM). KCNQ1 protein was demonstrated by immunoperoxidase labeling of pancreatic tissue, immunogold labeling of ZG, and immunoblotting of ZGM. 293B also inhibited cholecystokinin-induced amylase secretion of permeabilized acini (IC₅₀ of 10 µM). Thus KCNQ1 may account for ZG K⁺ conductance and contribute to pancreatic hormone-stimulated enzyme and fluid secretion.

exocytosis; acinar cell; secretory granule; planar bilayer