Upregulation of an inward rectifying K+ channel can rescue slow Ca2+ oscillations in K(ATP) channel deficient pancreatic islets

Yildirim, Vehpi; Vadrevu, Suryakiran; Thompson, Benjamin; Satin, Leslie S.; Bertram, Richard

doi:10.1371/journal.pcbi.1005686

Cited by 12 publications

(7 citation statements)

References 71 publications

(79 reference statements)

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“…Metabolic oscillations are synchronized across islets (37), but it is not known whether this is mediated by diffusion of metabolites across gap junctions or secondarily to synchronization of membrane potential and Ca 2+ . The mechanisms underlying observations of slow Ca 2+ oscillations in islets lacking K ATP channels (44,45) are also not yet established, but a compensation mechanism has been suggested (46); oscillations have been reported to occur in some islets deprived of K ATP channels for only 20 min, so compensation may be more rapid than previously appreciated (47). Finally, our focus on the slow oscillations leaves unclear the physiological significance of the fast oscillations.…”

Section: Discussionmentioning

confidence: 99%

Closing in on the Mechanisms of Pulsatile Insulin Secretion

2017

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Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.

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Section: Discussionmentioning

confidence: 99%

Closing in on the Mechanisms of Pulsatile Insulin Secretion

2017

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“…Stereotyped electrical activity is widespread in many different cell types, including bacteria 82 , 83 , pancreatic -cells 84 and cardiac cells 85 . Bursting oscillations play an integral role in insulin secretion by pancreatic -cells 84 , and these cells can compensate for genetic deletions of a critical channel K(ATP) channel population by over-expressing other potassium channels 86 in the mouse, but not in humans. Recent work suggests that these cells can use intracellular calcium as a sensor of voltage dynamics in a negative feedback loop to regulate activity 87 .…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Gorur-Shandilya

Marder

O’Leary

2020

Sci Rep

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In many species, excitable cells preserve their physiological properties despite significant variation in physical size across time and in a population. For example, neurons in crustacean central pattern generators generate similar firing patterns despite several-fold increases in size between juveniles and adults. This presents a biophysical problem because the electrical properties of cells are highly sensitive to membrane area and channel density. It is not known whether specific mechanisms exist to sense membrane area and adjust channel expression to keep a consistent channel density, or whether regulation mechanisms that sense activity alone are capable of compensating cell size. We show that destabilising effects of growth can be specifically compensated by feedback mechanism that senses average calcium influx and jointly regulate multiple conductances. However, we further show that this class of growth-compensating regulation schemes is necessarily sensitive to perturbations that alter the expression of subsets of ion channel types. Targeted perturbations of specific ion channels can trigger a pathological response of the regulation mechanism and a failure of homeostasis. Our findings suggest that physiological regulation mechanisms that confer robustness to growth may be specifically vulnerable to deletions or mutations that affect subsets of ion channels.

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“…Stereotyped electrical activity is widespread in many different cell types, including bacteria ( Masi et al, 2015 ; Kralj et al, 2011 ), pancreatic β -cells ( Bertram et al, 2010 ) and cardiac cells ( Hund and Rudy, 2000 ). Bursting oscillations play an integral role in insulin secretion by pancreatic β -cells ( Bertram et al, 2010 ), and these cells can compensate for genetic deletions of a critical channel K(ATP) channel population by over-expressing other potassium channels ( Yildirim et al, 2017 ) in the mouse, but not in humans. Recent work suggests that these cells can use intracellular calcium as a sensor of voltage dynamics in a negative feedback loop to regulate activity ( Yildirim and Bertram, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

Shandilya

Marder

O'Leary³

2019

Preprint

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Neurons can increase in size dramatically during growth. In many species neurons 8 must preserve their intrinsic dynamics and physiological function across several length scales. For 9 example, neurons in crustacean central pattern generators generate similar activity patterns 10 despite multiple-fold increases in their size and changes in morphology. This scale invariance hints 11 at regulation mechanisms that compensate for size changes by somehow altering membrane 12 currents. Using conductance-based neuron models, we asked whether simple activity-dependent 13 feedback can maintain intrinsic voltage dynamics in a neuron as its size is varied. Despite relying 14 only on a single sensor that measures time-averaged intracellular calcium as a proxy for activity, we 15 found that this regulation mechanism could regulate conductance densities of ion channels, and 16 was robust to changes in the size of the neuron. By mapping changes in cell size onto 17 perturbations in the space of conductance densities of all channels, we show how robustness to 18 size change coexists with sensitivity to perturbations that alter the ratios of maximum 19 conductances of different ion channel types. Our findings suggest that biological regulation that is 20 optimized for coping with expected perturbations such as size changes will be vulnerable to other 21 kinds of perturbations such as channel deletions. 22 29 three-fold increase in cell size (Bucher and Pflüger, 2000). RPeD1, a neuron in the respiratory 30 central pattern generator in Lymnaea, maintains resting membrane potential, spike amplitude 31 and membrane resistance despite two-fold growth from juvenile to adult (McComb et al., 2003). 32 In crickets, patterns of motor neuron output responsible for song production appear up to four 33 moults before the adult form (Bentley and Hoy, 1970). In lobsters, the co-ordinated bursting activity 34 of pyloric neurons is indistinguishable between juveniles and adults, despite a many-fold increase 35 in their size (Bucher et al., 2005). Even in embryonic stages, when these cells are even smaller, 36 the pyloric circuit central pattern generator (CPG) expresses spontaneous albeit less stereotyped 37 rhythmic activity (Casasnovas and Meyrand, 1995; Richards et al., 1999). 38 Neurons achieve their target behavior by expressing specific combinations of voltage and 39 calcium gated ion channels (Prinz et al., 2003). This leads to the question of how neurons maintain 40 1 of 20 Manuscript to be submitted to eLife a target function by regulating ion channel expression as the size of the cell increases. Can regulatory 41 mechanisms preserve neuron behavior during growth? 42 Homeostatic regulation has been proposed as a mechanism that can tune neuronal parameters 43 like ion channel densities to drive neuronal activity to some desired set point (LeMasson et al.,

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Upregulation of an inward rectifying K+ channel can rescue slow Ca2+ oscillations in K(ATP) channel deficient pancreatic islets

Cited by 12 publications

References 71 publications

Closing in on the Mechanisms of Pulsatile Insulin Secretion

Closing in on the Mechanisms of Pulsatile Insulin Secretion

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

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