Calcium-activated K+ Channels of Mouse β-cells are Controlled by Both Store and Cytoplasmic Ca2+

Abstract

A novel calcium-dependent potassium current (Kslow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic β-cells (Göpel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renström, and P. Rorsman. 1999. J. Gen. Physiol. 114:759–769). Kslow activation may help terminate the cyclic bursts of Ca2+-dependent action potentials that drive Ca2+ influx and insulin secretion in β-cells. Here, we report that when [Ca2+]i handling was disrupted by blocking Ca2+ uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1–5 μM) or insulin (200 nM), Kslow was transiently potentiated and then inhibited. Kslow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of Kslow by SERCA blockers could not be explained by a minimal mathematical model in which [Ca2+]i is divided between two compartments, the cytosol and the ER, and Kslow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which Kslow activation is mediated by a localized pool of [Ca2+] in a subspace located between the ER and the plasma membrane. In this model, the subspace [Ca2+] follows changes in cytosolic [Ca2+] but with a gradient that reflects Ca2+ efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of Kslow and [Ca2+] handling in influencing β-cell electrical activity and insulin secretion.

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

“…Inhibition of PKC (2 μ M Ro31-8220; Barman et al, 2004 ) combined with a block of SR Ca 2+ -ATPase (0.2 μ M thapsigargin; Goforth et al, 2002 ) caused a mild but consistent increase in current ( Fig. 7, B and G ), suggesting that PKC inhibition of myocyte BK channels ( Barman et al, 2004 ) prevails over channel activation by sarcoplasmic Ca 2+ ( Goforth et al, 2002 ) ( Fig.…”

“…7, B and G ), suggesting that PKC inhibition of myocyte BK channels ( Barman et al, 2004 ) prevails over channel activation by sarcoplasmic Ca 2+ ( Goforth et al, 2002 ) ( Fig. 8 ).…”

Complex bursting in pancreatic islets: a potential glycolytic mechanism

“…More recent models of bursting in b-cells include those by Chay (1996), Keizer and Smolen (1989), and Sherman et al (1988). In one recent b-cell model, the Phantom Bursting Model (PBM), bursting is driven by the interaction of more than one slow variable Goforth et al, 2002). In the PBM, the burst period ranges from a few seconds to a few minutes, depending upon the conductance of the various ionic currents.…”

“…Several models have been developed for bursting in pancreatic b-cells Chay, 1996;Chay and Keizer, 1983;Goforth et al, 2002;Keizer and Smolen, 1991;Sherman et al, 1988). These models differ primarily in the slow process responsible for driving the bursting.…”

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

“…Neither tolbutamide nor diazoxide had any effect on V m oscillations in K ATP null islets. The activation of a low-conductance, Ca 2+ -dependent K + current, termed "I Kslow ," has been implicated in the oscillatory activity of wild-type β cells [61,62]. Haspel et al [65] showed that Sur1KO β cells have a similar Ca 2+ -dependent K + current that is inhibited when [Ca 2+ ] c is reduced using D600, an L-type Ca 2+ channel blocker, and stimulated using BayK 8644, a Ca 2+ channel opener.…”