Abstract
Pancreatic β-cells secrete insulin in response to closure of ATP-sensitive K+ (KATP) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca2+ (Cai). In intact islets, β-cells are coupled by gap junctions, which are proposed to synchronize electrical activity and Cai oscillations after exposure to stimulatory glucose (>7 mM). To determine the significance of this coupling in regulating insulin secretion, we examined islets and β-cells from transgenic mice that express zero functional KATP channels in approximately 70% of their β-cells, but normal KATP channel density in the remainder. We found that KATP channel activity from approximately 30% of the β-cells is sufficient to maintain strong glucose dependence of metabolism, Cai, membrane potential, and insulin secretion from intact islets, but that glucose dependence is lost in isolated transgenic cells. Further, inhibition of gap junctions caused loss of glucose sensitivity specifically in transgenic islets. These data demonstrate a critical role of gap junctional coupling of KATP channel activity in control of membrane potential across the islet. Control via coupling lessens the effects of cell–cell variation and provides resistance to defects in excitability that would otherwise lead to a profound diabetic state, such as occurs in persistent neonatal diabetes mellitus.
Highlights
Introduction b-cells within the intact islet of Langerhans exhibit synchronous glucose-dependent bursts of electrical activity
It was previously shown that dispersed green fluorescent protein (GFP)-positive Kir6.2[AAA] b-cells are continuously depolarized in nonstimulatory glucose concentrations [9]
Our results demonstrate the mechanism by which the coupling of ATP-sensitive Kþ (KATP) channel activity via gap junctions results in near-normal glucose-dependent electrical and intracellular Ca2þ (Cai)
Summary
Critical Role of Gap Junction Coupled KATP Channel Activity for Regulated Insulin. Jonathan V. In comparison to WT, Kir6.2[AAA] islets showed no difference in baseline NAD(P)H intensity, but showed a slight (;1 mM) leftward shift in the (glucose) response (Figure 3B) This shift is comparable to that of glucose-stimulated Cai response and insulin secretion (see Figure 1D and 1E), suggesting a feedback modulation of metabolism during electrical activity. The data presented here indicate that glucose control of membrane potential, Cai, and insulin secretion all depend critically on the gap junctional coupling of KATP channel activity across neighboring cells within the islet (Figure 5). Our results demonstrate the mechanism by which the coupling of KATP channel activity via gap junctions results in near-normal glucose-dependent electrical and Cai. High (.6 mM) Glucose Concentrations (A) and (C) show the b-cell responses in the islet, and (B) and (D) show the dispersed b-cell responses.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
