Modulation of L-Type Ca2+ Channels by Distinct Domains Within SNAP-25

Ji, Junzhi; Yang, Shao Nian; Huang, Xiaohang; Li, Xidan; Sheu, Laura; Diamant, Nicholas E.; Berggren, Per Olof; Gaisano, Herbert Y.

doi:10.2337/diabetes.51.5.1425

Cited by 79 publications

(51 citation statements)

References 40 publications

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“…Because the t-SNAREs (syntaxin-1A and SNAP-25) also regulate rodent B-cell Ca 2ϩ (30) and K ϩ channels (voltage-dependent K ϩ -channel Kv2.1 and ATP-sensitive K ϩ channels) (31,32), which control the ionic events that trigger insulin exocytosis, perturbation of these ionic events by the reduced levels of SNARE proteins would contribute to the insulin secretory deficiency.…”

Section: Discussionmentioning

confidence: 99%

Impaired Gene and Protein Expression of Exocytotic Soluble N-Ethylmaleimide Attachment Protein Receptor Complex Proteins in Pancreatic Islets of Type 2 Diabetic Patients

et al. 2006

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Exocytosis of insulin is dependent on the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins in the B-cells. We assessed insulin release as well as gene and protein expression of SNARE complex protein in isolated pancreatic islets of type 2 diabetic patients (n ‫؍‬ 4) and nondiabetic control subjects (n ‫؍‬ 4). In islets from the diabetic patients, insulin responses to 8.3 and 16.7 mmol/l glucose were markedly reduced compared with control islets (4.7 ؎ 0.3 and 8.4 ؎ 1.8 vs. 17.5 ؎ 0.1 and 24.3 ؎ 1.2 U ⅐ islet ؊1 ⅐ h ؊1 , respectively; P < 0.001). Western blot analysis revealed decreased amounts of islet SNARE complex and SNARE-modulating proteins in diabetes: syntaxin-1A (21 ؎ 5% of control levels), SNAP-25 (12 ؎ 4%), VAMP-2 (7 ؎ 4%), nSec1 (Munc 18; 34 ؎ 13%), Munc 13-1 (27 ؎ 4%), and synaptophysin (64 ؎ 7%). Microarray gene chip analysis, confirmed by quantitative PCR, showed that gene expression was decreased in diabetes islets: syntaxin-1A (27 ؎ 2% of control levels), SNAP-25 (31 ؎ 7%), VAMP-2 (18 ؎ 3%), nSec1 (27 ؎ 5%), synaptotagmin V (24 ؎ 2%), and synaptophysin (12 ؎ 2%). In conclusion, these data support the view that decreased islet RNA and protein expression of SNARE and SNAREmodulating proteins plays a role in impaired insulin secretion in type 2 diabetic patients. It remains unclear, however, to which extent this defect is primary or secondary to, e.g., glucotoxicity. Diabetes 55: [435][436][437][438][439][440] 2006 I n addition to insulin resistance, impaired insulin response to glucose appears to be a prerequisite for type 2 diabetes to develop (1,2). For practical and ethical reasons, most studies of molecular mechanisms behind this functional B-cell defect have been performed in animal models of the disease. One such rodent is the Goto-Kakizaki (GK) rat, which is nonobese with moderate hyperglycemia on a background of greatly impaired insulin secretion and mildly to moderately decreased insulin sensitivity (3-5). Several metabolic abnormalities with potential impact on B-cell secretory function have been demonstrated in the pancreatic islets of GK rats (4,6 -9). Exocytosis of insulin is critically dependent on the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex proteins in the B-cells (10 -12). We have shown that expression of several of the SNARE complex proteins, such as VAMP-2, syntaxin-1A, SNAP-25, and nSec1 (Munc18), were decreased by ϳ40% in GK versus control rat islets (13,14), and similar impairments were also found in islets of the fa/fa Zucker rat (15). Moreover, in GK rat islets, dysregulation of SNARE complex protein expression was evident, because their compensatory increase by high-glucose exposure was abrogated (13).Here, we have investigated the role of the exocytotic SNARE complex proteins and several SNARE-modulating proteins in pancreatic islets obtained from patients with type 2 diabetes compared with nondiabetic control subjects. For that purpose, we studied the gene expression by Affymetrix microarray chip...

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Section: Discussionmentioning

confidence: 99%

Impaired Gene and Protein Expression of Exocytotic Soluble N-Ethylmaleimide Attachment Protein Receptor Complex Proteins in Pancreatic Islets of Type 2 Diabetic Patients

et al. 2006

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“…SNARE proteins may therefore serve to orchestrate the sequence of ionic and exocytic events leading to secretion. Indeed, in the neuroendocrine islet beta cells, syntaxin 1A (Syn-1A) and SNAP-25 modulate voltage-gated Ca 2ϩ (10,11) and voltage-gated K ϩ channels (Kv2.1) (12). Recently, we have reported that Syn-1A also inhibits K ATP channels in pancreatic islet beta cells, through its actions on the NBF-1 of SUR1 (13).…”

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H3 Domain of Syntaxin 1A Inhibits KATP Channels by Its Actions on the Sulfonylurea Receptor 1 Nucleotide-Binding Folds-1 and -2

Cui

Kang

et al. 2004

Journal of Biological Chemistry

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The ATP-sensitive potassium (K ATP ) channel in pancreatic islet beta cells consists of four pore-forming (Kir6.2) subunits and four regulatory sulfonylurea receptor (SUR1) subunits. In beta cells, the K ATP channel links intracellular metabolism to the dynamic regulation of the cell membrane potential that triggers insulin secretion. Syntaxin 1A (Syn-1A) is a SNARE protein that not only plays a direct role in exocytosis, but also binds and modulates voltage-gated K ؉ and Ca 2؉ channels to fine tune exocytosis. We recently reported that wild type Syn-1A inhibits rat islet beta cell K ATP channels and binds both nucleotide-binding folds (NBF-1 and NBF-2) of SUR1. However, wild type Syn-1A inhibition of rat islet beta cell K ATP channels seems to be mediated primarily via NBF-1. During exocytosis, Syn-1A undergoes a conformational change from a closed form to an open form, which would fully expose its active domain, the C-terminal H3 domain. Here, we show that the constitutively open form Syn-1A

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“…First, unlike the β cell Ca V 1.2 and Ca V 1.3 channels, which are tightly coupled to the exocytotic machinery (13)(14)(15), the Ca V 2.3 channel seems to be distant from the areas in the β cell where insulin-containing granules fuse with the plasma membrane and release their contents. Neither the deletion of the Ca V 2.3 subunit gene nor the pharmacological ablation of the Ca V 2.3 channel altered the exocytotic profile of insulincontaining granules from the immediately releasable pool.…”

Section: Figurementioning

confidence: 99%