CaV2.3 channel and PKCλ: new players in insulin secretion

Yang, Shao Nian; Berggren, Per Olof

doi:10.1172/jci23970

Cited by 16 publications

(6 citation statements)

References 35 publications

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“…These channels could be involved in recruiting insulin-containing granules from pools that are not immediately available to release their content (46,95).…”

Section: Voltage-sensitive Channelsmentioning

confidence: 99%

Channel regulation of glucose sensing in the pancreatic β-cell

Hiriart¹,

Aguilar‐Bryan²

2008

American Journal of Physiology-Endocrinology and Metabolism

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Mammalian ␤-cells are acutely and chronically regulated by sensing surrounding glucose levels that determine the rate at which insulin is secreted, to maintain euglycemia. Experimental research in vitro and in vivo has shown that, when these cells are exposed to adverse conditions like long periods of hypoglycemia or hyperglycemia, their capability to sense glucose is decreased. Understanding the normal physiology and identifying the main players along this route becomes paramount. In this review, we have taken on the task of looking at the role that ion channels play in the regulation of this process, delineating the different families, and describing the signaling that parallels the glucose sensing process that results in insulin release. transient receptor potential; sodium current; calcium current; insulin secretion; insulin secretion coupling PANCREATIC ␤-CELLS secrete insulin in response to a "sensing" mechanism triggered by an increase in extracellular glucose from basal levels. Stimulation-secretion coupling in ␤-cells is different from other cell types because instead of being mediated by receptor binding, glucose needs to be transported into the cytoplasm and metabolized to stimulate exocytosis. Previous reviews (76, 51) have divided the glucose-sensing apparatus into proximal metabolic and distal ionic apparatus. The proximal component includes glucose transport through a specific transporter on the ␤-cell membrane (GLUT1 for humans, GLUT2 for rodents) followed by the glycolytic pathway, which results in an increase in the ATP/ADP ratio that triggers the distal component comprising a cascade of electrochemical events that culminate in an increase in intracellular calcium ([Ca 2ϩ ] i ) and stimulation of insulin secretion. This process can be augmented by several enteroinsular hormones [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and CCK] and neurotransmitters like acetylcholine, which amplify the secretory response through the activation of adenylate cyclase or phospholipase C.During fasting, basal glucose levels are ϳ5-6 mM, and the ␤-cell membrane is polarized at resting potential. Dean and Matthews (17,18), almost four decades ago, were the first to show that when glucose rises voltage across the membrane oscillates, generating electrical activity leading to an increase in [Ca 2ϩ ] i and subsequent insulin secretion. This activity consists of an initial slow membrane depolarization, followed by a fast depolarization and subsequent plateau level on which bursts of action potentials are superimposed to finally repolarize the plasma membrane, which returns to its initial polarized state at resting potential. This oscillating process regenerates as long as the glucose concentration is elevated and results from the activity of ion channels localized to the ␤-cell plasma membrane. Insulin is an anabolic hormone, essential for the maintenance of glucose homeostasis, because, among other effects, insulin increases glucose uptake in many cell types to promote nu...

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“…These channels could be involved in recruiting insulin-containing granules from pools that are not immediately available to release their content (46,95).…”

Section: Voltage-sensitive Channelsmentioning

confidence: 99%

Channel regulation of glucose sensing in the pancreatic β-cell

Hiriart¹,

Aguilar‐Bryan²

2008

American Journal of Physiology-Endocrinology and Metabolism

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“…Opening of L-type calcium channels leads to a higher intracellular calcium concentration, which triggers insulin exocytosis. 10 We observed that after the treatment the …”

Section: Pip2mentioning

confidence: 89%

“…This triggers a membrane depolarization, leading to voltage sensitive Na + and type T Ca 2+ channels opening, and finally to the activation of L type Ca 2+ channels, which have the largest conductance. 10 The resulting increase in intracellular Ca 2+ triggers insulin exocytosis (for a review, see ref. 11).…”

Section: Introductionmentioning

confidence: 99%

Metabolic syndrome induces changes in K_ATP-channels and calcium currents in pancreatic β-cells

Velasco

Larqué

Gutiérrez-Reyes

et al. 2012

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“…Ca V 2.3 is one non–L-type high-voltage-activated (HVA) channel belonging to the voltage-gated Ca 2+ channel family, whose members mediate Ca 2+ entry into cells in response to membrane depolarization [1] .…”

Section: Introductionmentioning

confidence: 99%

“…Ca V 2.3, which is expressed primarily in neuronal cells [2] and in pancreatic beta cells [1] , plays a key role in second-phase insulin release [3] . Silencing Ca V 2.3 expression in INS-1 cells blunts glucose-stimulated insulin secretion [4] .…”

Section: Introductionmentioning

confidence: 99%

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

et al. 2012

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BackgroundGenetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca2+ channel CaV2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes.Methodology/Principal FindingsIn 595 GAD-negative, drug naïve patients (mean±SD; age: 58.5±10.2 yrs; BMI: 29.9±5 kg/m2, HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05−0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05).Conclusions/SignificanceIn patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.

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CaV2.3 channel and PKCλ: new players in insulin secretion

Cited by 16 publications

References 35 publications

Channel regulation of glucose sensing in the pancreatic β-cell

Channel regulation of glucose sensing in the pancreatic β-cell

Metabolic syndrome induces changes in K_ATP-channels and calcium currents in pancreatic β-cells

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

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CaV2.3 channel and PKCλ: new players in insulin secretion

Cited by 16 publications

References 35 publications

Channel regulation of glucose sensing in the pancreatic β-cell

Channel regulation of glucose sensing in the pancreatic β-cell

Metabolic syndrome induces changes in KATP-channels and calcium currents in pancreatic β-cells

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

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Metabolic syndrome induces changes in K_ATP-channels and calcium currents in pancreatic β-cells