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Electrophysiology of the β Cell and Mechanisms of Inhibition of Insulin Release

Mark J. Dunne, Carina Ämmälä, Susanne G. Straub, Geoffrey W. G. Sharp

10.1002/cphy.cp070204

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Ion Channels in Insulin‐Secreting Cells
1.1 Adenosine Triphosphate–Sensitive Potassium Channels
1.2 Extracellular Control of Adenosine Triphosphate‐Sensitive Potassium Channel Function
1.3 Therapeutic Manipulation by Modulators of Adenosine Triphosphate‐Sensitive Potassium Channels
1.4 Architecture of the β‐cell Adenosine Triphosphate‐Sensitive Potassium Channel
1.5 Calcium‐Selective Ion Channels
1.6 Voltage‐Gated Sodium Channels
1.7 Voltage‐Gated Potassium Channels
1.8 Voltage‐Independent Potassium Channels
1.9 Nonselective Cation Channels
1.10 Anion‐Selective Channels
2 Ionic Defects of β‐Cell Function
2.1 Persistent Hyperinsulinemic Hypoglycemia of Infancy
2.2 Altered Ionic Control of β Cells and Hypersecretion of Insulin
2.3 Correlation of Gene Defects in the Adenosine Triphosphate‐Sensitive Potassium Channel with Persistent Hyperinsulinemic Hypoglycemia of Infancy
2.4 Clinical Therapy for Persistent Hyperinsulinemic Hypoglycemia of Infancy
2.5 Implications for Diabetes Mellitus
3 Stimulus‐Secretion Coupling Mechanisms Other Than Depolarization
4 Novel Methods for the Measurement of Insulin Secretion
4.1 Capacitance
4.2 Amperometry and Voltametry
4.3 Calcium and Exocytosis
4.4 Cyclic Adenosine Monophosphate and Exocytosis
4.5 Effects of Phospholipases and Protein Kinases C and A
4.6 Sulfonylureas and Exocytosis
4.7 G Proteins and Exocytosis
4.8 Other Modulators of Exocytosis
4.9 Modeling Calcium‐, Cyclic, and Adenosine Monophosphate–, and Guanosine Triphosphate–Dependent Exocytosis
5 Molecular Mechanisms of Exocytosis in the β Cell
6 Receptor‐Mediated Inhibition of Insulin Release: Early and Late Effects
6.1 Involvement of G Proteins
6.2 Receptor–G Protein Interactions
7 Inhibitory Mechanisms
7.1 Adenosine Triphosphate–Sensitive Potassium Channel Activation and Membrane Repolarization
7.2 Calcium Channel Inhibition
7.3 Inhibition of Adenylate Cyclase
7.4 Inhibition at a Distal Site
8 G Protein–Target Interactions
8.1 Adenosine Triphosphate–Sensitive Potassium Channel
8.2 L‐Type Calcium Channels
8.3 Adenylate Cyclase
8.4 Distal Inhibitory Site
9 Other Possible Mechanisms
9.1 Inhibition of Glucose Metabolism
9.2 Inhibition of Fatty Acid Metabolism
9.3 Stimulation of Calcium–Adenosine Triphosphatase Activity
9.4 Cyclic Guanosine Monophosphate
9.5 Cytoskeleton
10 Summary of Inhibitory Mechanisms
Figure 1. Figure 1.

Function of the KATP channel in β cells. The model simplifies the fundamental role of KATP, channels in insulin‐secreting cells: control of the resting membrane potential by open KATP channels, while glucose‐dependent closure facilitates depolarization of the membrane and subsequent opening of voltage‐gated Ca2+ channels. The model details neither the function of other ion channels nor the action of glucose upon secretion by mechanisms independent of KATP, channel activity. Glut glucose transporter.
Figure 2. Figure 2.

Molecular architecture of the KATP channel in β cells. The model shows two subunits: sulfonylurea receptor (SUR1) which has a predicted topology of multiple membrane‐spanning domains and two nucleotide‐binding folds, and Kir6.2, a K+ channel. Subunit SUR1 has two glycosylation sites (both thought to be extracellularly disposed) and an extracellular N‐terminal sequence.
Figure 3. Figure 3.

Ion channels in β cells. The major ion channels characterized in insulin‐secreting cells: several K+‐selective channels, such as the ATP‐sensitive K+ channel (KATP), the Ca2+‐ and voltage‐gated K+ channel (KCa or Kmaxi), the delayed‐rectifier K+ channel (KV), the low‐conductance/receptor‐operated K+ channel (KI), and the outward‐rectifier K+ channel, (KA); Ca2+ selective L‐type and T‐type voltage‐gated channels; cation‐selective channels (Ca2+ store‐depleted and KNS); voltage‐gated Na+ channels; and C1‐ channels modulated by intracellular Ca2+ and cAMP. The KATP channels are shown as being critically important for linking glucose metabolism to the initiation of cell depolarization, which is then required for Ca2+‐dependent exocytosis. Δψ voltage‐gated.
Figure 4. Figure 4.

Ion channel records from intact normal and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) human β cells. Experiments were made under exactly the same conditions; note the presence of KATP channels as upward deflections from the baseline in normal cells but not in β cells from the patient. Loss of KATP channel function is associated with the appearance of verapamil‐inhibited Ca2+ action potentials. Both records were made using cell‐attached patch‐clamp techniques (see cartoon) and are plotted, for clarity, on the same scale.

[From Kane et al. 138 with permission.]
Figure 5. Figure 5.

Isolated inside‐out patch records from normal and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells that confirm the absence of functional KATP channels in patient tissue. Both traces show the time course of events that typically follow inside‐out patch formation. In normal tissue, a KATP, current typically develops as ATP is lost from the inside face of the membrane. No currents are seen in PHHI β cells under exactly the same conditions.

[From Kane et al. 138 with permission.]
Figure 6. Figure 6.

“Spontaneous” action potentials in persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells. Recording of these clusters of electrical responses occur in the absence of stimulatory concentrations of glucose.

[From Kane et al. 138 with permission.]
Figure 7. Figure 7.

Model to account for hypersecretion of insulin from persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells. Loss of KATP channel function leads to spontaneously electrically active cells as the result of a depolarized cell membrane potential. Hyperactivity of Ca2+ channels is predicted to cause constant Ca2+ influx, leading to initiation of insulin release.
Figure 8. Figure 8.

Reported sites of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) mutations in sulfonylurea receptor (SUR1) and Kir6.2 (insert) In SUR1, these mutations are clustered about the nucleotide‐binding folds (NBFs) and result in loss of Walker A/B consensus sequences. See text for further descriptions of mutations. Arrows indicate mutations in SUR1 NBF1 described by Thomas and colleagues 274 and the intron 32 mutation leading to a truncation of the SUR1 gene product.
Figure 9. Figure 9.

Organization of sulfonylurea receptor (SUR1) and the corresponding position of exons 1–39. TM1 and TM2, regions of putative “transmembrane” spanning domains (see also fig. 2). Nucleotide‐binding Fold 1 (NBF1) and NBF2 are encoded for by exons 16–21 and 34–37, respectively. Arrows indicate the positions of familial persistent hyperinsulinemic hypoglycemia of infancy mutations, which are collected around the NBF1 and NBF2, the principal sites of SUR1 regulation. Shaded arrowhead represents the intron 32 mutation.
Figure 10. Figure 10.

Model to account for how an ion channel‐based therapy for persistent hyperinsulinemic hypoglycemia of infancy (PHHI) might achieve normoglycemia. The strategy is directed toward termination of voltage‐gated Ca2+ influx. This could be brought about by direct inhibition of channels 172 or by hyperpolarizing the membrane away from the threshold for activation of Ca2+ channels. The latter scenario could result from direct agonists of K+ channels or receptor‐mediated events that involve K+ channel activation and/or Ca2+ channel inhibition. Glut, glucose transporter.
Figure 11. Figure 11.

Major pathways involved in stimulation of insulin release. Shown is the KATP channel‐dependent pathway in which increased blood glucose concentrations and consequent increased β‐cell metabolism result in a charge in the intracellular ATP: ADP ratio. This is thought to be a major contributory factor in the closure of ATP‐dependent K+ channels, depolarization of the β cell membrane and increased L‐type Ca2+ channel activity. Increased channel activity and accelerated Ca2+ influx result in elevation of intracellular Ca2+ and stimulated insulin release. Also shown are the important KATP channel‐independent pathways which augment the Ca2+‐stimulated insulin release of the KATP channel‐dependent pathway and the combined stimulation by protein kinases A (PKA) and C (PKC). Major potentiation of release results from hormonal and peptidergic activation of receptors positively linked to adenylate cyclase. Examples of such receptors are those for vasoactive intestinal peptide (VIP), pituitary adenylate cyclase‐activating peptide (PACAP), and glucagon‐like peptide (GLP‐1). Occupation of these receptors by hormones results in activation of adenylate cyclase, increased cAMP levels, and potentiation of release by two mechanisms: (1) activation of PKA and phosphorylation of the L‐type Ca2+ channel to increase Ca2+ entry and (2) phosphorylation at an as yet unknown distal site in stimulus‐secretion coupling to enhance stimulated release. A third potentiating mechanism is activation of receptors linked to phospholipase C, increased phosphoinositide hydrolysis, and increased production of inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DAG). As is the case for adenylate cyclase stimulation, the two products of phospholipase C activity result in increased [Ca2+]i (by mobilization of intracellular Ca2+) and potentiation of insulin release by PKC activation and phosphorylation of another, as yet unknown distal site in stimulus‐secretion coupling. This figure has been drawn simply, to illustrate only the major pathways and sites at which the physiological inhibitors may act. CCK, cholecystokinin.
Figure 12. Figure 12.

Methodologies for capacitance studies. These can be carried out with cell‐attached patch experiments (A), standard whole‐cell experiments (B), or perforated patch whole‐cell experiments (C). D: Schematic representation of the change in cell membrane area during either exocytosis or endocytosis. This change is proportional to the cell capacitance.
Figure 13. Figure 13.

Experimental setup for capacitance measurements. A: Cell membrane of a secretory granule before (top) and after (bottom) exocytosis. The area of the plasma membrane increases due to incorporation of the granular membrane. B: Experimental design of capacitance measurements. To the left is the electrical equivalent of the cell (Gm, Cm) in series with the recording pipette (Gs). When the cell is stimulated with a varying sinusoidal command voltage (V), the resulting sinusoidal current will be phase‐shifted (Θ) relative to V due to the capacitative and conductive properties of the cell. The recorded current is fed into a computer and analyzed at two orthogonal vectors. By finding the correct phase angle (Theta;), the current representing the capacitative (ICm) current and the conductive (IG = IGs + IGm) current can be separated. Changes in cell capacitance (ΔCm) and conductance (ΔG) can therefore be detected as changes in ICm and IG, respectively.
Figure 14. Figure 14.

Dual recordings of insulin secretion from a single β cell A: Changes in capacitance induced by Ca2+ currents elicited by a train of voltage‐clamp depolarizations (200 ms, 1 Hz). B: Initiation of exocytosis is associated with a concomitant decrease in fluorescence of quinacrine, an agent used to fluorescently label the secretory granules of β cells.
Figure 15. Figure 15.

Regulation of exocytosis by local Ca2+ concentration in the vicinity of Ca2+ channels. A(i): When the Ca2+ channel opens, Ca2+ immediately reaches a high concentration in the active zone and exocytosis is initiated. A(ii): Upon closure of the Ca2+ channel, local Ca2+ transient and exocytosis stop though a fluorescence Ca2+ indicator may continue to report elevated intracellular Ca2+ signals for some time. B(i): In the absence of the Ca2+ chelator EGTA, Ca2+ influx through open Ca2+ channels both inactivates Ca2+ channels and initiates exocytosis, while in the presence of EGTA (ii) Ca2+ still inactivates the channel but, due to the diffusion path, exocytosis is abolished.
Figure 16. Figure 16.

cAMP potentiation of Ca2+‐stimulated insulin release. In these experiments, exocytosis is stimulated by the photorelease of cAMP (80 μM) from a caged precursor 6. Cells were infused with Ca2+–EGTA mixtures, yielding a final [Ca2+]i concentration of (A) O mM, (B) 60 nM, or (C) 2 μM. The same concentration of cAMP causes a more marked stimulation of exocytosis at a higher Ca2+ concentration.
Figure 17. Figure 17.

Exocytosis. Multiple components play a role in the late stages of stimulus‐secretion coupling and exocytosis. A (top): The unstimulated state is shown with the insulin‐containing granule and the vesicle‐associated membrane protein (VAMP)/synaptobrevin and synaptotagmin components. The rab3 protein thought to be involved in trafficking, NSF (N‐ethylmaleimide‐sensitive factor), and SNAPS (soluble NSF‐attachment proteins) are also shown. On the plasma membrane are syntaxin, Munc‐18, and SNAP‐25. For docking shown in A (bottom), the VAMP/synaptobrevin (the v‐SNARE) in the granule membrane binds to syntaxin and SNAP‐25 (the two making up the t‐SNARE) in the plasma membrane. As Munc‐18 inhibits the binding of the v‐ and t‐SNAREs, the binding, or “docking,” requires the prior dissociation of Munc‐18. Synaptotagmin association with the complex is also thought to be inhibitory, and dissociation of synaptotagmin from the complex occurs during “priming,” as shown in B (top). Subsequently, NSF and SNAP(s) complete the formation of the fusion complex that leads finally to exocytosis [B (bottom)]. SNAP‐25, synaptosome‐associated protein of Mr 25,000; Munc‐18, mammalian homologue of the Caenorhabditis elegans unc‐18 gene.

[Adapted from refs. 89, 236, 259, and 266, using only those components known to be present in the β cell and presumed to be involved in exocytosis.]
Figure 18. Figure 18.

The G‐protein cycle in the pancreatic β cell in relation to inhibitory ligands and effector G‐protein targets. Receptor activation by agonists such as norepinephrine, somatostatin, galanin, and prostaglandins induces them to bind and destabilize specific heterotrimeric G proteins (GαGDPβγ). Decreased affinity for GDP and increased affinity for GTP result in GDP–GTP exchange on the α subunit of the G protein and subsequent dissociation of the α and βγ subunits into their active forms. Actions of the α and βγ subunits on the target molecules (the channels, adenylate cyclase, and the distal mechanism) are responsible for inhibition of insulin release. These actions are terminated by the inherent GTPase activity of the α subunits, probably under the control; of GTPase‐activating proteins (GAPs) and/or the GAP activity of the targets. Hydrolysis of GTP allows reformation of the heterotrimeric (GDP‐bound) G protein. The cycle is complete when the G protein interacts again with an activated receptor.
Figure 19. Figure 19.

Sites of inhibition of insulin release in the β cell. The four major sites of inhibitory action: The KATP channel, which is activated by inhibitors to repolarize the β cell; the L‐type Ca2+ channel, which is closed as the β cell repolarizes and may be subject to a minor level of direct inhibition (both effects lead to a decrease in [Ca2+], and inhibition of secretion); adenylate cyclase, the activity of which is decreased by the inhibitors, resulting in a lowering of [Ca2+]i and loss of the potentiating effect of cAMP; and the distal site of inhibition, which, while powerful and well documented, is not yet understood. VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase‐activating peptide; GLP‐1, glucagon‐like peptide 1.
Figure 20. Figure 20.

Multiple inhibitory agonists, multiple G‐protein mediators, and multiple effector systems which result in inhibition of insulin release. There are multiple inhibitors of insulin secretion, which may act simultaneously on the β cell. As there are five pertussis toxin‐sensitive G proteins that may mediate the inhibitory effects, the receptors share and compete according to relative amounts of receptors and individual G proteins, their affinities for them, and their subcellular location. Activated G proteins then seek out their several targets of inhibitory action. Shown are examples of inhibitory ligands, the three Gi and two Go proteins that may be present in β cells, the four well‐documented sites of inhibitory action (KATP channel, L‐type Ca2+ channel, adenylate cyclase, and the distal site), and other suggested sites of inhibitory action. CGRP, calcitonin gene–related peptide.


Figure 1.

Function of the KATP channel in β cells. The model simplifies the fundamental role of KATP, channels in insulin‐secreting cells: control of the resting membrane potential by open KATP channels, while glucose‐dependent closure facilitates depolarization of the membrane and subsequent opening of voltage‐gated Ca2+ channels. The model details neither the function of other ion channels nor the action of glucose upon secretion by mechanisms independent of KATP, channel activity. Glut glucose transporter.



Figure 2.

Molecular architecture of the KATP channel in β cells. The model shows two subunits: sulfonylurea receptor (SUR1) which has a predicted topology of multiple membrane‐spanning domains and two nucleotide‐binding folds, and Kir6.2, a K+ channel. Subunit SUR1 has two glycosylation sites (both thought to be extracellularly disposed) and an extracellular N‐terminal sequence.



Figure 3.

Ion channels in β cells. The major ion channels characterized in insulin‐secreting cells: several K+‐selective channels, such as the ATP‐sensitive K+ channel (KATP), the Ca2+‐ and voltage‐gated K+ channel (KCa or Kmaxi), the delayed‐rectifier K+ channel (KV), the low‐conductance/receptor‐operated K+ channel (KI), and the outward‐rectifier K+ channel, (KA); Ca2+ selective L‐type and T‐type voltage‐gated channels; cation‐selective channels (Ca2+ store‐depleted and KNS); voltage‐gated Na+ channels; and C1‐ channels modulated by intracellular Ca2+ and cAMP. The KATP channels are shown as being critically important for linking glucose metabolism to the initiation of cell depolarization, which is then required for Ca2+‐dependent exocytosis. Δψ voltage‐gated.



Figure 4.

Ion channel records from intact normal and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) human β cells. Experiments were made under exactly the same conditions; note the presence of KATP channels as upward deflections from the baseline in normal cells but not in β cells from the patient. Loss of KATP channel function is associated with the appearance of verapamil‐inhibited Ca2+ action potentials. Both records were made using cell‐attached patch‐clamp techniques (see cartoon) and are plotted, for clarity, on the same scale.

[From Kane et al. 138 with permission.]


Figure 5.

Isolated inside‐out patch records from normal and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells that confirm the absence of functional KATP channels in patient tissue. Both traces show the time course of events that typically follow inside‐out patch formation. In normal tissue, a KATP, current typically develops as ATP is lost from the inside face of the membrane. No currents are seen in PHHI β cells under exactly the same conditions.

[From Kane et al. 138 with permission.]


Figure 6.

“Spontaneous” action potentials in persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells. Recording of these clusters of electrical responses occur in the absence of stimulatory concentrations of glucose.

[From Kane et al. 138 with permission.]


Figure 7.

Model to account for hypersecretion of insulin from persistent hyperinsulinemic hypoglycemia of infancy (PHHI) β cells. Loss of KATP channel function leads to spontaneously electrically active cells as the result of a depolarized cell membrane potential. Hyperactivity of Ca2+ channels is predicted to cause constant Ca2+ influx, leading to initiation of insulin release.



Figure 8.

Reported sites of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) mutations in sulfonylurea receptor (SUR1) and Kir6.2 (insert) In SUR1, these mutations are clustered about the nucleotide‐binding folds (NBFs) and result in loss of Walker A/B consensus sequences. See text for further descriptions of mutations. Arrows indicate mutations in SUR1 NBF1 described by Thomas and colleagues 274 and the intron 32 mutation leading to a truncation of the SUR1 gene product.



Figure 9.

Organization of sulfonylurea receptor (SUR1) and the corresponding position of exons 1–39. TM1 and TM2, regions of putative “transmembrane” spanning domains (see also fig. 2). Nucleotide‐binding Fold 1 (NBF1) and NBF2 are encoded for by exons 16–21 and 34–37, respectively. Arrows indicate the positions of familial persistent hyperinsulinemic hypoglycemia of infancy mutations, which are collected around the NBF1 and NBF2, the principal sites of SUR1 regulation. Shaded arrowhead represents the intron 32 mutation.



Figure 10.

Model to account for how an ion channel‐based therapy for persistent hyperinsulinemic hypoglycemia of infancy (PHHI) might achieve normoglycemia. The strategy is directed toward termination of voltage‐gated Ca2+ influx. This could be brought about by direct inhibition of channels 172 or by hyperpolarizing the membrane away from the threshold for activation of Ca2+ channels. The latter scenario could result from direct agonists of K+ channels or receptor‐mediated events that involve K+ channel activation and/or Ca2+ channel inhibition. Glut, glucose transporter.



Figure 11.

Major pathways involved in stimulation of insulin release. Shown is the KATP channel‐dependent pathway in which increased blood glucose concentrations and consequent increased β‐cell metabolism result in a charge in the intracellular ATP: ADP ratio. This is thought to be a major contributory factor in the closure of ATP‐dependent K+ channels, depolarization of the β cell membrane and increased L‐type Ca2+ channel activity. Increased channel activity and accelerated Ca2+ influx result in elevation of intracellular Ca2+ and stimulated insulin release. Also shown are the important KATP channel‐independent pathways which augment the Ca2+‐stimulated insulin release of the KATP channel‐dependent pathway and the combined stimulation by protein kinases A (PKA) and C (PKC). Major potentiation of release results from hormonal and peptidergic activation of receptors positively linked to adenylate cyclase. Examples of such receptors are those for vasoactive intestinal peptide (VIP), pituitary adenylate cyclase‐activating peptide (PACAP), and glucagon‐like peptide (GLP‐1). Occupation of these receptors by hormones results in activation of adenylate cyclase, increased cAMP levels, and potentiation of release by two mechanisms: (1) activation of PKA and phosphorylation of the L‐type Ca2+ channel to increase Ca2+ entry and (2) phosphorylation at an as yet unknown distal site in stimulus‐secretion coupling to enhance stimulated release. A third potentiating mechanism is activation of receptors linked to phospholipase C, increased phosphoinositide hydrolysis, and increased production of inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DAG). As is the case for adenylate cyclase stimulation, the two products of phospholipase C activity result in increased [Ca2+]i (by mobilization of intracellular Ca2+) and potentiation of insulin release by PKC activation and phosphorylation of another, as yet unknown distal site in stimulus‐secretion coupling. This figure has been drawn simply, to illustrate only the major pathways and sites at which the physiological inhibitors may act. CCK, cholecystokinin.



Figure 12.

Methodologies for capacitance studies. These can be carried out with cell‐attached patch experiments (A), standard whole‐cell experiments (B), or perforated patch whole‐cell experiments (C). D: Schematic representation of the change in cell membrane area during either exocytosis or endocytosis. This change is proportional to the cell capacitance.



Figure 13.

Experimental setup for capacitance measurements. A: Cell membrane of a secretory granule before (top) and after (bottom) exocytosis. The area of the plasma membrane increases due to incorporation of the granular membrane. B: Experimental design of capacitance measurements. To the left is the electrical equivalent of the cell (Gm, Cm) in series with the recording pipette (Gs). When the cell is stimulated with a varying sinusoidal command voltage (V), the resulting sinusoidal current will be phase‐shifted (Θ) relative to V due to the capacitative and conductive properties of the cell. The recorded current is fed into a computer and analyzed at two orthogonal vectors. By finding the correct phase angle (Theta;), the current representing the capacitative (ICm) current and the conductive (IG = IGs + IGm) current can be separated. Changes in cell capacitance (ΔCm) and conductance (ΔG) can therefore be detected as changes in ICm and IG, respectively.



Figure 14.

Dual recordings of insulin secretion from a single β cell A: Changes in capacitance induced by Ca2+ currents elicited by a train of voltage‐clamp depolarizations (200 ms, 1 Hz). B: Initiation of exocytosis is associated with a concomitant decrease in fluorescence of quinacrine, an agent used to fluorescently label the secretory granules of β cells.



Figure 15.

Regulation of exocytosis by local Ca2+ concentration in the vicinity of Ca2+ channels. A(i): When the Ca2+ channel opens, Ca2+ immediately reaches a high concentration in the active zone and exocytosis is initiated. A(ii): Upon closure of the Ca2+ channel, local Ca2+ transient and exocytosis stop though a fluorescence Ca2+ indicator may continue to report elevated intracellular Ca2+ signals for some time. B(i): In the absence of the Ca2+ chelator EGTA, Ca2+ influx through open Ca2+ channels both inactivates Ca2+ channels and initiates exocytosis, while in the presence of EGTA (ii) Ca2+ still inactivates the channel but, due to the diffusion path, exocytosis is abolished.



Figure 16.

cAMP potentiation of Ca2+‐stimulated insulin release. In these experiments, exocytosis is stimulated by the photorelease of cAMP (80 μM) from a caged precursor 6. Cells were infused with Ca2+–EGTA mixtures, yielding a final [Ca2+]i concentration of (A) O mM, (B) 60 nM, or (C) 2 μM. The same concentration of cAMP causes a more marked stimulation of exocytosis at a higher Ca2+ concentration.



Figure 17.

Exocytosis. Multiple components play a role in the late stages of stimulus‐secretion coupling and exocytosis. A (top): The unstimulated state is shown with the insulin‐containing granule and the vesicle‐associated membrane protein (VAMP)/synaptobrevin and synaptotagmin components. The rab3 protein thought to be involved in trafficking, NSF (N‐ethylmaleimide‐sensitive factor), and SNAPS (soluble NSF‐attachment proteins) are also shown. On the plasma membrane are syntaxin, Munc‐18, and SNAP‐25. For docking shown in A (bottom), the VAMP/synaptobrevin (the v‐SNARE) in the granule membrane binds to syntaxin and SNAP‐25 (the two making up the t‐SNARE) in the plasma membrane. As Munc‐18 inhibits the binding of the v‐ and t‐SNAREs, the binding, or “docking,” requires the prior dissociation of Munc‐18. Synaptotagmin association with the complex is also thought to be inhibitory, and dissociation of synaptotagmin from the complex occurs during “priming,” as shown in B (top). Subsequently, NSF and SNAP(s) complete the formation of the fusion complex that leads finally to exocytosis [B (bottom)]. SNAP‐25, synaptosome‐associated protein of Mr 25,000; Munc‐18, mammalian homologue of the Caenorhabditis elegans unc‐18 gene.

[Adapted from refs. 89, 236, 259, and 266, using only those components known to be present in the β cell and presumed to be involved in exocytosis.]


Figure 18.

The G‐protein cycle in the pancreatic β cell in relation to inhibitory ligands and effector G‐protein targets. Receptor activation by agonists such as norepinephrine, somatostatin, galanin, and prostaglandins induces them to bind and destabilize specific heterotrimeric G proteins (GαGDPβγ). Decreased affinity for GDP and increased affinity for GTP result in GDP–GTP exchange on the α subunit of the G protein and subsequent dissociation of the α and βγ subunits into their active forms. Actions of the α and βγ subunits on the target molecules (the channels, adenylate cyclase, and the distal mechanism) are responsible for inhibition of insulin release. These actions are terminated by the inherent GTPase activity of the α subunits, probably under the control; of GTPase‐activating proteins (GAPs) and/or the GAP activity of the targets. Hydrolysis of GTP allows reformation of the heterotrimeric (GDP‐bound) G protein. The cycle is complete when the G protein interacts again with an activated receptor.



Figure 19.

Sites of inhibition of insulin release in the β cell. The four major sites of inhibitory action: The KATP channel, which is activated by inhibitors to repolarize the β cell; the L‐type Ca2+ channel, which is closed as the β cell repolarizes and may be subject to a minor level of direct inhibition (both effects lead to a decrease in [Ca2+], and inhibition of secretion); adenylate cyclase, the activity of which is decreased by the inhibitors, resulting in a lowering of [Ca2+]i and loss of the potentiating effect of cAMP; and the distal site of inhibition, which, while powerful and well documented, is not yet understood. VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase‐activating peptide; GLP‐1, glucagon‐like peptide 1.



Figure 20.

Multiple inhibitory agonists, multiple G‐protein mediators, and multiple effector systems which result in inhibition of insulin release. There are multiple inhibitors of insulin secretion, which may act simultaneously on the β cell. As there are five pertussis toxin‐sensitive G proteins that may mediate the inhibitory effects, the receptors share and compete according to relative amounts of receptors and individual G proteins, their affinities for them, and their subcellular location. Activated G proteins then seek out their several targets of inhibitory action. Shown are examples of inhibitory ligands, the three Gi and two Go proteins that may be present in β cells, the four well‐documented sites of inhibitory action (KATP channel, L‐type Ca2+ channel, adenylate cyclase, and the distal site), and other suggested sites of inhibitory action. CGRP, calcitonin gene–related peptide.

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Article Title: Electrophysiology of the β Cell and Mechanisms of Inhibition of Insulin Release
 

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Mark J. Dunne, Carina Ämmälä, Susanne G. Straub, Geoffrey W. G. Sharp. Electrophysiology of the β Cell and Mechanisms of Inhibition of Insulin Release. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 79-123. First published in print 2001. doi: 10.1002/cphy.cp070204