Abstract
BackgroundThe divalent cation Calcium (Ca2+) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca2+ directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca2+-regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis. Scope of reviewThis review aims to briefly highlight canonical Ca2+ signaling pathways in β-cells and how β-cells regulate the movement of Ca2+ across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca2+ signaling pathways for β-cell function and health. Major conclusionsAcute increases in intracellular Ca2+ stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca2+ signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca2+ signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca2+ movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.
Highlights
Major conclusions: Acute increases in intracellular Ca2þ stimulate a number of signaling cascades, resulting inphosphorylation events and activation of downstream transcription factors
Decades of study demonstrate that Ca2þ movement is tightly regulated within the b-cell, which is at least partially due to its dual roles as a potent signaling molecule
ryanodine receptors (RyRs) contribute to glucose-stimulated insulin secretion by mediating the process of Ca2þ-induced Ca2þ release (CICR) [32] through several possible mechanisms, depending on which Ca2þ store expresses RyRs
Summary
Elevated cytosolic Ca2þ (Ca2þi) initiates a broad range of physiological responses in excitatory cells, from promoting exocytosis in endocrine cells and neurons to muscle contraction in myocytes. RyRs contribute to glucose-stimulated insulin secretion by mediating the process of Ca2þ-induced Ca2þ release (CICR) [32] through several possible mechanisms, depending on which Ca2þ store expresses RyRs. With ER-localized RyRs, CICR is thought to increase Ca2þi in close proximity to mitochondria and maintain high rates of ATP generation. Ca2þ influx into the mitochondria during periods of high metabolic demands ensures adequate ATP production to maintain insulin secretion by increasing the availability of metabolic substrates and stimulating the TCA cycle (possibly through activation of 2-oxoglutarate dehydrogenase and isocitrate dehydrogenase) [45]. Together, these studies demonstrate the importance of tightly regulated mitochondrial Ca2þ levels. The potency of Ca2þ as a signaling molecule is a major reason for this degree of intricacy
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