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Cited by 137Pancreatic function and diabetesIon channel regulation and functionCardiac electrophysiology and arrhythmias

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Activation of Ca2+-Dependent K+ Channels Contributes to Rhythmic Firing of Action Potentials in Mouse Pancreatic β Cells

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Göpel, Sven O., Kanno, Takahiro, Barg, Sebastian, Eliasson, Lena, Galvanovskis, Juris, Renström, Erik, Rorsman, Patrik·1999·The Journal of General Physiology
DOI 10.1085/jgp.114.6.759PMC PMC2230648
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Abstract

We have applied the perforated patch whole-cell technique to β cells within intact pancreatic islets to identify the current underlying the glucose-induced rhythmic firing of action potentials. Trains of depolarizations (to simulate glucose-induced electrical activity) resulted in the gradual (time constant: 2.3 s) development of a small (<0.8 nS) K+ conductance. The current was dependent on Ca2+ influx but unaffected by apamin and charybdotoxin, two blockers of Ca2+-activated K+ channels, and was insensitive to tolbutamide (a blocker of ATP-regulated K+ channels) but partially (>60%) blocked by high (10–20 mM) concentrations of tetraethylammonium. Upon cessation of electrical stimulation, the current deactivated exponentially with a time constant of 6.5 s. This is similar to the interval between two successive bursts of action potentials. We propose that this Ca2+-activated K+ current plays an important role in the generation of oscillatory electrical activity in the β cell.

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Figures

Figure 1 Train of action potentials elicits an outward current in β cells. (A) Membrane potential oscillations in a β cell exposed to 10 mM glucose. The glucose concentration was lowered to 5 mM as indicated above the voltage trace. *The amplifier was switched from the current-clamp into the voltage-clamp mode, the membrane potential held at −70 mV, and the command voltage varied as indicated. (B) The membrane currents elicited by the pulse train (C, top). Note time-dependent decline of outward current. (C, bottom) Change of holding current displayed on an expanded vertical scale. Note gradual development of a holding current. Same experiment as in B. (D) Membrane potential recording from the same cell as in C before lowering the glucose concentration. In C and D, the vertical line marks the temporal relationship between cessation of stimulation and the onset of rapid repolarization (left) and the onset of rapid depolarization during the subsequent burst (right). The horizontal lines indicate (from top to bottom) the steady state holding current at −40 mV, the plateau potential from which the cell repolarizes upon termination of the burst, and the most negative membrane potential attained between two bursts. (E) Membrane potential recording from an isolated (dispersed) β cell maintained in tissue culture. The glucose concentration was changed from 10 to 0 mM as indicated above the voltage trace. (F) Currents elicited by the train of depolarizations (bottom) in the presence of 10 (top) and 5 (middle) mM glucose. The inward current (indicated by the horizontal line above the current trace) is due to a burst of action potentials generated in a neighboring β cell. Note that step current elicited when stepping from −70 to −40 mV is larger at 5 than at 10 mM glucose, reflecting greater activity of the KATP channels.
Figure 1 Train of action potentials elicits an outward current in β cells. (A) Membrane potential oscillations in a β cell exposed to 10 mM glucose. The glucose concentration was lowered to 5 mM as indicated above the voltage trace. *The amplifier was switched from the current-clamp into the voltage-clamp mode, the membrane potential held at −70 mV, and the command voltage varied as indicated. (B) The membrane currents elicited by the pulse train (C, top). Note time-dependent decline of outward current. (C, bottom) Change of holding current displayed on an expanded vertical scale. Note gradual development of a holding current. Same experiment as in B. (D) Membrane potential recording from the same cell as in C before lowering the glucose concentration. In C and D, the vertical line marks the temporal relationship between cessation of stimulation and the onset of rapid repolarization (left) and the onset of rapid depolarization during the subsequent burst (right). The horizontal lines indicate (from top to bottom) the steady state holding current at −40 mV, the plateau potential from which the cell repolarizes upon termination of the burst, and the most negative membrane potential attained between two bursts. (E) Membrane potential recording from an isolated (dispersed) β cell maintained in tissue culture. The glucose concentration was changed from 10 to 0 mM as indicated above the voltage trace. (F) Currents elicited by the train of depolarizations (bottom) in the presence of 10 (top) and 5 (middle) mM glucose. The inward current (indicated by the horizontal line above the current trace) is due to a burst of action potentials generated in a neighboring β cell. Note that step current elicited when stepping from −70 to −40 mV is larger at 5 than at 10 mM glucose, reflecting greater activity of the KATP channels.CC BY-NC-SA · PubMed Central
Figure 2 Kslow current is K+ selective. (A, bottom) After the train of depolarizations, the membrane potential was held for 10 s at voltages between −40 and −80 mV as indicated schematically by the pulse protocol. (A, top) Membrane currents recorded at −50 mV after the train when the extracellular medium contained 3.6 or 15 mM K+ as indicated. Note that the currents go in opposite directions. (B) The peak tail currents recorded at membrane potentials between −80 and −40 mV before and after elevation of extracellular K+ from 3.6 mM (▪) to 15 mM (▴). The amplitude of the current was measured as illustrated in B. The arrows indicate the reversal potentials recorded at low and high extracellular K+.
Figure 2 Kslow current is K+ selective. (A, bottom) After the train of depolarizations, the membrane potential was held for 10 s at voltages between −40 and −80 mV as indicated schematically by the pulse protocol. (A, top) Membrane currents recorded at −50 mV after the train when the extracellular medium contained 3.6 or 15 mM K+ as indicated. Note that the currents go in opposite directions. (B) The peak tail currents recorded at membrane potentials between −80 and −40 mV before and after elevation of extracellular K+ from 3.6 mM (▪) to 15 mM (▴). The amplitude of the current was measured as illustrated in B. The arrows indicate the reversal potentials recorded at low and high extracellular K+.CC BY-NC-SA · PubMed Central
Figure 3 Cell coupling does not account for Kslow current. (A) Membrane potential recording from a β cell in an intact islet. (B) Voltage-clamp recording at a holding potential of −70 mV. Changes of the cell conductance (G) were determined from the current responses (top) elicited by application of ±10-mV voltage pulses (200-ms duration, 2 Hz frequency; bottom). (C) Cell conductance calculated from the ±10-mV voltage steps in B. Note that the cell conductance is stable and amounts to ≈1 nS. In B and C, the shaded area indicated the silent interval between two successive bursts. (D) Current responses (top) elicited by a train of depolarizations followed by a series of ±10-mV voltage pulses applied from a holding potential of −70 mV to monitor the cell conductance (bottom). (E) Cell conductance (G) calculated from the ±10-mV voltage pulses. Note that the conductance is greatest (2.1 nS) immediately after the train, but subsequently declines to the steady state value (1.3 nS). The same cell was used in A–E.
Figure 3 Cell coupling does not account for Kslow current. (A) Membrane potential recording from a β cell in an intact islet. (B) Voltage-clamp recording at a holding potential of −70 mV. Changes of the cell conductance (G) were determined from the current responses (top) elicited by application of ±10-mV voltage pulses (200-ms duration, 2 Hz frequency; bottom). (C) Cell conductance calculated from the ±10-mV voltage steps in B. Note that the cell conductance is stable and amounts to ≈1 nS. In B and C, the shaded area indicated the silent interval between two successive bursts. (D) Current responses (top) elicited by a train of depolarizations followed by a series of ±10-mV voltage pulses applied from a holding potential of −70 mV to monitor the cell conductance (bottom). (E) Cell conductance (G) calculated from the ±10-mV voltage pulses. Note that the conductance is greatest (2.1 nS) immediately after the train, but subsequently declines to the steady state value (1.3 nS). The same cell was used in A–E.CC BY-NC-SA · PubMed Central
Figure 4 Pharmacological characterization of Kslow. (A) Failure of tolbutamide (100 μM) to affect current amplitude. Note that the current response observed when stepping from −70 to −40 mV is reduced by tolbutamide reflecting closure of KATP channels (shaded areas). The horizontal lines indicate the peak amplitude and steady state current, respectively. (B) Effects of TEA (20 mM). The horizontal dotted lines indicate (from top to bottom) the peak current amplitude, under control conditions and in the presence of TEA, and the steady state current, respectively. (C) Concentration dependence of inhibitory action of TEA. The Kslow conductance (G) is expressed as the fractional current using the current amplitude in TEA-free solution as unity (Gcontrol). Note that inhibition is half-maximal at 5 mM and that 30% of the current is resistant to TEA. (D) Electrical activity evoked by 15 mM glucose in the same cell before and after addition of TEA.
Figure 4 Pharmacological characterization of Kslow. (A) Failure of tolbutamide (100 μM) to affect current amplitude. Note that the current response observed when stepping from −70 to −40 mV is reduced by tolbutamide reflecting closure of KATP channels (shaded areas). The horizontal lines indicate the peak amplitude and steady state current, respectively. (B) Effects of TEA (20 mM). The horizontal dotted lines indicate (from top to bottom) the peak current amplitude, under control conditions and in the presence of TEA, and the steady state current, respectively. (C) Concentration dependence of inhibitory action of TEA. The Kslow conductance (G) is expressed as the fractional current using the current amplitude in TEA-free solution as unity (Gcontrol). Note that inhibition is half-maximal at 5 mM and that 30% of the current is resistant to TEA. (D) Electrical activity evoked by 15 mM glucose in the same cell before and after addition of TEA.CC BY-NC-SA · PubMed Central
Figure 5 Association between [Ca2+]i and Kslow current activation. (A) Membrane current (top) elicited by a train of depolarizations (bottom) and the associated changes of the cytoplasmic [Ca2+]i in an isolated cell (white trace superimposed on current trace). The horizontal line indicate steady state current and [Ca2+]i. (B) The current amplitude measured at the end of the train in isolated cells and in β cells within intact islets. *P < 0.001. (C) Kslow current (top) elicited by the train of depolarizations (bottom) under control conditions and in the presence of 200 μM Cd2+. (D) Voltage-gated Ca2+ currents recorded during 100-ms depolarizations to 0 mV from a holding potential of −70 mV in β cells in intact islets (top) and in dispersed β cells (middle). (E) Charge entry normalized to cell capacitance (Q/C)–voltage (V) relationships of the Ca2+ current recorded in isolated β cells (▴) and in β cells within intact islets (▪). Mean values ± SEM of 8 (▪) and 15 (▴) experiments. *P < 0.05.
Figure 5 Association between [Ca2+]i and Kslow current activation. (A) Membrane current (top) elicited by a train of depolarizations (bottom) and the associated changes of the cytoplasmic [Ca2+]i in an isolated cell (white trace superimposed on current trace). The horizontal line indicate steady state current and [Ca2+]i. (B) The current amplitude measured at the end of the train in isolated cells and in β cells within intact islets. *P < 0.001. (C) Kslow current (top) elicited by the train of depolarizations (bottom) under control conditions and in the presence of 200 μM Cd2+. (D) Voltage-gated Ca2+ currents recorded during 100-ms depolarizations to 0 mV from a holding potential of −70 mV in β cells in intact islets (top) and in dispersed β cells (middle). (E) Charge entry normalized to cell capacitance (Q/C)–voltage (V) relationships of the Ca2+ current recorded in isolated β cells (▴) and in β cells within intact islets (▪). Mean values ± SEM of 8 (▪) and 15 (▴) experiments. *P < 0.05.CC BY-NC-SA · PubMed Central
Figure 6 Parallel recordings of glucose-induced changes of the membrane potential and membrane conductance in a β cell within an intact islet. (A) Membrane potential recorded in the absence of glucose, after elevation of glucose to 15 mM, and in the simultaneous presence of 15 mM glucose and 100 μM tolbutamide. At the times indicated (1–3), the amplifier was switched from the current-clamp into the voltage-clamp mode and the membrane conductance was monitored by application of ±10-mV voltage pulses (duration: 500 ms; frequency: 0.5 Hz). (B) Membrane currents measured during the voltage steps to −80 mV. The current responses shown in A–C were taken as indicated in A. (C) Net change of whole-cell KATP produced by 0.1 mM tolbutamide added in the presence of 10 or 15 mM glucose and the amplitude of the Kslow current elicited by a train of depolarizations.
Figure 6 Parallel recordings of glucose-induced changes of the membrane potential and membrane conductance in a β cell within an intact islet. (A) Membrane potential recorded in the absence of glucose, after elevation of glucose to 15 mM, and in the simultaneous presence of 15 mM glucose and 100 μM tolbutamide. At the times indicated (1–3), the amplifier was switched from the current-clamp into the voltage-clamp mode and the membrane conductance was monitored by application of ±10-mV voltage pulses (duration: 500 ms; frequency: 0.5 Hz). (B) Membrane currents measured during the voltage steps to −80 mV. The current responses shown in A–C were taken as indicated in A. (C) Net change of whole-cell KATP produced by 0.1 mM tolbutamide added in the presence of 10 or 15 mM glucose and the amplitude of the Kslow current elicited by a train of depolarizations.CC BY-NC-SA · PubMed Central

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Research works printed but not linked: 2

  1. Göpel, 1998, Activation of a Ca2+-activated K+-conductance terminates the burst of action potentials in insulin-secreting pancreatic B-cells, Diabetologia., 41, 540
  2. Satin, 1994, Electrical bursting in β-cell of the pancreatic islets of Langerhans, Endocrine, 2, 677

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Metadata

Authors
Göpel, S. O., Kanno, T., Barg, S., Eliasson, L., Galvanovskis, J., Renström, E., & Rorsman, P.
Affiliations
Lund University (SE)
ORCID
Venue
The Journal of General Physiology
Publisher
Rockefeller University Press
Published
1999-11-15
Volume
114
Issue
6
Pages
759-770
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
DOI
10.1085/jgp.114.6.759
PMC
PMC2230648
OpenAlex
W2065171939
Cited by
137
References
40
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 5
FWCI
4.91
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of General Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
calcium-activated potassium channels, pancreatic beta cells, pancreatic islets, tetraethylammonium, ATP-sensitive potassium channels, apamin, charybdotoxin, tolbutamide, potassium conductance, bursting oscillations
MeSH terms
Action Potentials, Animals, Electrophysiology, Hypoglycemic Agents, Islets of Langerhans, Membrane Potentials, Tolbutamide, Potassium Channels, Patch-Clamp Techniques, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, Potassium Channels, Calcium-Activated, Potassium Channel Blockers, Large-Conductance Calcium-Activated Potassium Channels, Mice, KATP Channels, In Vitro Techniques

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