Spatial Organization of Ca2+ Entry and Exocytosis in Mouse Pancreatic β-Cells

Qian, Weijun; Kennedy, Robert T.

doi:10.1006/bbrc.2001.5379

Cited by 24 publications

(20 citation statements)

References 32 publications

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“…This value is surprisingly high because the average cytosolic (global) Ca 2π in the B-cell does not exceed ∂2 mM during stimulation (Ämmälä et al 1993;Bokvist et al 1995;Dryselius et al 1999). Obviously, steep spatial Ca 2π -gradients must exist and exocytosis is probably triggered in these zones where [Ca 2π ] i may be 10 times higher than in the remainder of the cell (Bokvist et al 1995;Qian & Kennedy 2001).…”

Section: Minireviewmentioning

confidence: 98%

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Barg

2003

Pharmacology & Toxicology

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In pancreatic B-and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca 2π -influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca 2π -influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (Ͻ1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further ''priming'' for release by several ATP-and Ca 2π -dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca 2π -channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.

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Section: Minireviewmentioning

confidence: 98%

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Barg

2003

Pharmacology & Toxicology

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“…One of the most important unknowns is the nature of the step that determines whether a granule is in the IR pool or not. Suggestions include the need for a close association with Ca 2ϩ channels or specific exocytotic sites (4,5,39,41,51) and changes in Ca 2ϩ sensitivity so that exocytosis occurs at lower [Ca 2ϩ ] i . In addition to the IR pool, granules in the RR pool can be mobilized rapidly by cyclic AMP (37).…”

Section: The Model and The Hypothesismentioning

confidence: 99%

Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion

Straub

Sharp

2004

American Journal of Physiology-Cell Physiology

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The biphasic secretory response of pancreatic beta-cells to abrupt and sustained exposure to glucose is well documented. Some of the ATP-sensitive K(+) (K(ATP)) channel-dependent mechanisms underlying the first phase of insulin release are known; the mechanisms underlying the second phase are less well known. The hypothesis we propose is that one rate-limiting step, controlling the conversion of granules in a readily releasable (RR) docked granule pool to an immediately releasable (IR) pool, is responsible for the magnitude of both phases of release. Furthermore, we propose that the K(ATP) channel-independent signaling pathway regulates this rate-limiting step. The size of the IR pool of granules that constitutes the first phase is determined under resting conditions by the forward and reverse rates of conversion of granules in the RR and IR pools. The resulting equilibrium position determines the maximum number of beta-cell granules available for release during the first phase upon exposure to glucose. At the nadir between the two phases, the IR pool has been depleted so that the rate of granule release is equal to the low forward rate for the conversion of RR to IR granules. After the nadir, the forward rate is accelerated during the rising portion of the second phase until it reaches a maximum rate at the plateau.

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“…Insulin-containing secretory granules and L-type VDCCs are colocalized in ␤-cells (Bokvist et al, 1995;Qian and Kennedy, 2001). The functional coupling between L-type channels and exocytotic granules may resemble that of non-L-type VDCCs to neurotransmitter release in neurons.…”

mentioning

confidence: 99%

Ca_v1.3 Is Preferentially Coupled to Glucose-Stimulated Insulin Secretion in the Pancreatic β-Cell Line INS-1

Liu¹,

Dilmac²,

Hilliard³

et al. 2003

J Pharmacol Exp Ther

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Spatial Organization of Ca2+ Entry and Exocytosis in Mouse Pancreatic β-Cells

Cited by 24 publications

References 32 publications

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion

Ca_v1.3 Is Preferentially Coupled to Glucose-Stimulated Insulin Secretion in the Pancreatic β-Cell Line INS-1

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Spatial Organization of Ca2+ Entry and Exocytosis in Mouse Pancreatic β-Cells

Cited by 24 publications

References 32 publications

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion

Cav1.3 Is Preferentially Coupled to Glucose-Stimulated Insulin Secretion in the Pancreatic β-Cell Line INS-1

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Ca_v1.3 Is Preferentially Coupled to Glucose-Stimulated Insulin Secretion in the Pancreatic β-Cell Line INS-1