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Role of high-voltage-activated calcium channels in glucose-regulated β-cell calcium homeostasis and insulin release

Published on Nov 1, 2005in American Journal of Physiology-endocrinology and Metabolism 4.13
· DOI :10.1152/ajpendo.00101.2005
James T. Taylor9
Estimated H-index: 9
Luping Huang7
Estimated H-index: 7
+ 3 AuthorsMing Li23
Estimated H-index: 23
High-voltage-activated (HVA) calcium channels are known to be the primary source of calcium for glucose-stimulated insulin secretion. However, few studies have investigated how these channels can be regulated by chronically elevated levels of glucose. In the present study, we determined the level of expression of the four major HVA calcium channels (N-type, P/Q-type, LC-type, and LD-type) in rat pancreatic β-cells. Using quantitative real-time PCR (QRT-PCR), we found the expression of all four HVA genes in rat insulinoma cells (INS-1) and in primary isolated rat islet cells. We then determined the role of each channel in insulin secretion by using channel-selective antagonists. Insulin secretion analysis revealed that N- and L-type channels are both involved in immediate glucose-induced insulin secretion. However, L-type was preferentially coupled to secretion at later time points. P/Q-type channels were not found to play a role in insulin secretion at any stage. It was also found that long-term exposure ...
  • References (70)
  • Citations (23)
Published on Jun 28, 2008in European Journal of Clinical Investigation 2.78
Bo Hellman54
Estimated H-index: 54
(Uppsala University),
Christian Berne55
Estimated H-index: 55
+ 3 AuthorsPer-Eric Lund15
Estimated H-index: 15
(Uppsala University)
. The effects of glucose on the cytoplasmic Ca2+ concentration (Ca2+i) regulating insulin release were investigated using pancreatic β-cells representative for the normal and diabetic situations. Increase of the glucose concentration resulted in a slight lowering of Ca2+i followed by a rise, often manifested as high amplitude oscillations. The Ca2+i-lowering component in the glucose action associated with suppression of insulin release became particularly prominent when the β-cells were already ...
Published on Apr 1, 2005in Pediatric Research 2.88
Ming Li23
Estimated H-index: 23
Min Zhang7
Estimated H-index: 7
+ 5 AuthorsRichard M Whitehurst6
Estimated H-index: 6
T-Type Ca 2+ Channels Are Involved in High Glucose–Induced Rat Neonatal Cardiomyocyte Proliferation
Published on Jan 3, 2005in Journal of Clinical Investigation 12.28
Xingjun Jing11
Estimated H-index: 11
Dai-Qing Li5
Estimated H-index: 5
+ 9 AuthorsToni Schneider33
Estimated H-index: 33
Concerted activation of different voltage-gated Ca2+ channel isoforms may determine the kinetics of insulin release from pancreatic islets. Here we have elucidated the role of R-type CaV2.3 channels in that process. A 20% reduction in glucose-evoked insulin secretion was observed in CaV2.3-knockout (CaV2.3–/–) islets, close to the 17% inhibition by the R-type blocker SNX482 but much less than the 77% inhibition produced by the L-type Ca2+ channel antagonist isradipine. Dynamic insulin-release me...
Published on Oct 1, 2004in Biophysical Journal 3.67
Vahid Shahrezaei13
Estimated H-index: 13
(SFU: Simon Fraser University),
Kerry R. Delaney25
Estimated H-index: 25
(SFU: Simon Fraser University)
Morphological and biochemical studies indicate association between voltage-gated Ca2+ channels and the vesicle docking complex at vertebrate presynaptic active zones, which constrain the separation between some Ca2+ channels and vesicles to 20 nm or less. To address the effect of the precise geometrical relationship among the vesicles, the Ca2+ channel, and the proteins of the release machinery on neurotransmitter release, we developed a Monte Carlo simulation of Ca2+ diffusion and buffering wit...
Published on Jul 1, 2004in The Journal of Membrane Biology 1.75
David Mears10
Estimated H-index: 10
(USU: Uniformed Services University of the Health Sciences)
Insulin secretion from β-cells of the pancreatic islets of Langerhans is triggered by Ca2+ influx through voltage-dependent Ca2+ channels. Electrophysiological and molecular studies indicate that β-cells express several subtypes of these channels. This review discusses their roles in regulating insulin secretion, focusing on recent studies using β-cells, exogenous expression systems, and Ca2+ channel knockout mice. These investigations reveal that L-type Ca2+ channels in the β-cell physically in...
Published on Jan 16, 2004in Journal of Pharmacology and Experimental Therapeutics 3.62
Luping Huang7
Estimated H-index: 7
Brian M. Keyser8
Estimated H-index: 8
+ 6 AuthorsMing Li23
Estimated H-index: 23
Mibefradil is a Ca 2+ channel antagonist that inhibits both T-type and high-voltage-activated Ca 2+ channels. We previously showed that block of high-voltage-activated channels by mibefradil occurs through the production of an active metabolite by intracellular hydrolysis. In the present study, we modified the structure of mibefradil to develop a nonhydrolyzable analog, (1 S , 2 S )-2-(2-( N -[(3-benzimidazol-2-yl)propyl]- N -methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl c...
Published on Apr 1, 2004in Diabetes 7.20
A. Wendt19
Estimated H-index: 19
Bryndis Birnir28
Estimated H-index: 28
+ 5 AuthorsMatthias Braun28
Estimated H-index: 28
gamma-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat beta-cells release GABA by Ca(2+)-dependent exocytosis ...
Published on Feb 1, 2004in American Journal of Physiology-cell Physiology 3.55
Luping Huang7
Estimated H-index: 7
Arin Bhattacharjee22
Estimated H-index: 22
+ 4 AuthorsMing Li23
Estimated H-index: 23
Chronic exposure of pancreatic β-cells to high concentrations of glucose impairs the insulin secretory response to further glucose stimulation. This phenomenon is referred to as glucose desensitization. It has been shown that glucose desensitization is associated with abnormal elevation of β-cell basal intracellular free Ca2+ concentration ([Ca2+]i). We have investigated the relationship between the basal intracellular free Ca2+ and the L-type (Cav1.3) Ca2+ channel translocation in insulin-secre...
Published on Nov 19, 2003in The Journal of Neuroscience 6.07
Darrin H. Brager16
Estimated H-index: 16
(UMB: University of Maryland, Baltimore),
Paul W. Luther6
Estimated H-index: 6
(UMB: University of Maryland, Baltimore)
+ 2 AuthorsBradley E. Alger44
Estimated H-index: 44
(UMB: University of Maryland, Baltimore)
Regulation of GABA release is crucial for normal brain functioning, and GABA A -mediated IPSCs are strongly influenced by repetitive stimulation and neuromodulation. However, GABA exocytosis has not been examined directly in organized tissue. Important issues remain outside the realm of electrophysiological techniques or are complicated by postsynaptic factors. For example, it is not known whether all presynaptic modulators affect release from all boutons in the same way, or whether modulator ef...
Published on Nov 1, 2003in Neuropharmacology 4.37
C Cantí1
Estimated H-index: 1
(UCL: University College London),
Annette C. Dolphin64
Estimated H-index: 64
(UCL: University College London)
Voltage-dependent Ca2+ channels (VDCCs) are subject to modulation by a number of pathways, including membrane-delimited inhibition by heterotrimeric G-proteins and modulation through phosphorylation by diverse kinases. Here we report that in the Xenopus oocyte expression system Ca(v)2.2 channels undergo a sustained, linear and irreversible run-up lasting up to 30 min, which is potentiated during G-protein-mediated inhibition by activation of co-expressed G-protein coupled receptors (GPCRs). This...
Cited By23
Published in Journal of Clinical Investigation 12.28
Kunihiko Araki3
Estimated H-index: 3
Amane Araki7
Estimated H-index: 7
+ -3 AuthorsKazuhiro Ikumi1
Estimated H-index: 1
Published on May 14, 2019in Molecules 3.06
Beatriz Elena Sarmiento1
Estimated H-index: 1
Luis Felipe Santos Menezes , Elisabeth F. Schwartz21
Estimated H-index: 21
Venom from mammals, amphibians, snakes, arachnids, sea anemones and insects provides diverse sources of peptides with different potential medical applications. Several of these peptides have already been converted into drugs and some are still in the clinical phase. Diabetes type 2 is one of the diseases with the highest mortality rate worldwide, requiring specific attention. Diverse drugs are available (e.g., Sulfonylureas) for effective treatment, but with several adverse secondary effects, mo...
Published on Nov 1, 2018in Journal of Cellular Physiology 4.52
Hyeon-Jeong Hwang1
Estimated H-index: 1
(UNIST: Ulsan National Institute of Science and Technology),
Kyoung-Su Park1
Estimated H-index: 1
(UNIST: Ulsan National Institute of Science and Technology)
+ 3 AuthorsPann-Ghill Suh33
Estimated H-index: 33
(UNIST: Ulsan National Institute of Science and Technology)
Published on Sep 1, 2018in Journal of Immunological Methods 1.91
Ahmed M. Alshehri (Flinders Medical Centre), Thilini Mendis (Flinders Medical Centre), Michael W. Jackson17
Estimated H-index: 17
(Flinders Medical Centre)
Abstract Recent studies have postulated the presence of functional autoantibodies (Abs) against L-type voltage gated calcium channels (VGCCs) in the serum of patients with type 1 diabetes, with various proposed physiological consequences, both islet cell associated and extra-glandular. Arguably, the most potentially damaging effect reported for these Abs is induction of apoptosis in pancreatic beta (β) cells, yet a convincing pathogenic mechanism remains to be demonstrated. In the current study,...
Published on Aug 17, 2016in Molecular Pharmacology 3.85
Myrian Velasco7
Estimated H-index: 7
(UNAM: National Autonomous University of Mexico),
Carlos Manlio Diaz-Garcia7
Estimated H-index: 7
(UNAM: National Autonomous University of Mexico)
+ 1 AuthorsMarcia Hiriart21
Estimated H-index: 21
(UNAM: National Autonomous University of Mexico)
Pancreatic beta cells play a significant role in glucose homeostasis; they are the unique cells that secrete insulin in response to an increase in glucose levels. Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells has been extensively explored. In this mechanism, glucose enters the cells and then the metabolic cycle; during this process the ATP/ADP ratio increase, leading to the closure of KATP channels. KATP channels closure initiates depolarization, which is also dependent on...
Published on Feb 5, 2016in PLOS ONE 2.78
Li Xie13
Estimated H-index: 13
(U of T: University of Toronto),
Subhankar Dolai12
Estimated H-index: 12
(U of T: University of Toronto)
+ 6 AuthorsHerbert Y. Gaisano43
Estimated H-index: 43
(U of T: University of Toronto)
Syntaxin (Syn)-1A mediates exocytosis of predocked insulin-containing secretory granules (SGs) during first-phase glucose-stimulated insulin secretion (GSIS) in part via its interaction with plasma membrane (PM)-bound L-type voltage-gated calcium channels (Cav). In contrast, Syn-3 mediates exocytosis of newcomer SGs that accounts for second-phase GSIS. We now hypothesize that the newcomer SG Syn-3 preferentially binds and modulates R-type Cav opening, which was postulated to mediate second-phase...
Published on Oct 1, 2015in Biochemical Journal 4.33
Akos A. Gerencser24
Estimated H-index: 24
(Touro University California),
Hindrik Mulder48
Estimated H-index: 48
(Lund University),
David G. Nicholls82
Estimated H-index: 82
(Lund University)
In the presence of high glucose or pyruvate, INS-1 832/13 insulinoma cells undergo stochastic oscillations in plasma membrane potential (Δψ p ) leading to associated fluctuations in cytosolic free Ca 2+ concentration ([Ca 2+ ] c ). Oscillations are not driven by upstream metabolic fluctuations, but rather by autonomous ionic mechanisms, the details of which are unclear. We have investigated the nature of the oscillator, with simultaneous fluorescence monitoring of Δψ p , [Ca 2+ ] c and exocytosi...
Published on Jul 1, 2015in Pharmacology & Therapeutics 9.40
Koichiro Kuwahara40
Estimated H-index: 40
(Kyoto University),
Takeshi Kimura65
Estimated H-index: 65
(Kyoto University)
Abstract The six subtypes of voltage-dependent Ca 2+ channels (VDCCs) mediate a wide range of physiological responses. N-type VDCCs (NCCs) were originally identified as a high voltage-activated Ca 2+ channel selectively blocked by omega-conotoxin (ω-CTX)-GVIA. Predominantly localized in the nervous system, NCCs are key regulators of neurotransmitter release. Both pharmacological blockade with ω-CTX-GVIA and, more recently, mice lacking CNCNA1B , encoding the α1B subunit of NCC, have been used to...
Published on Jan 1, 2015
Ming Li (Tulane University)
Increases in plasma glucose concentration enhance the expression and activity of T-type Ca2+ channels in insulin-secreting pancreatic β-cells. The resulting elevation in T-type Ca2+ channel activity results in an elevation in the basal [Ca2+]i of β-cells. High [Ca2+]i in turn causes the internalization of L-type Ca2+ channels from cytoplasmic membrane, which contributes to glucose toxicity in β-cells. Increased activity of T-type Ca2+ channels, along with elevated [Ca2+]i, promotes low threshold...
Published on Jul 25, 2013in PLOS ONE 2.78
Zuheng Ma5
Estimated H-index: 5
(KI: Karolinska Institutet),
Noah Moruzzi6
Estimated H-index: 6
(KI: Karolinska Institutet)
+ 4 AuthorsAnneli Björklund10
Estimated H-index: 10
(KI: Karolinska Institutet)
Objective Beta cells of pancreatic islets are susceptible to functional deficits and damage by hypoxia. Here we aimed to characterize such effects and to test for and pharmacological means to alleviate a negative impact of hypoxia. Methods and Design Rat and human pancreatic islets were subjected to 5.5 h of hypoxia after which functional and viability parameters were measured subsequent to the hypoxic period and/or following a 22 h re-oxygenation period. Preconditioning with diazoxide or other ...