scholarly journals Role of High Voltage-Gated Ca2+ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2004
Author(s):  
Petronel Tuluc ◽  
Tamara Theiner ◽  
Noelia Jacobo-Piqueras ◽  
Stefanie M. Geisler
Keyword(s):  
Pancreatic Islets ◽  
High Voltage ◽  
Secretory Granules ◽  
Cell Mass ◽  
Cell Activity ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Voltage Gated ◽  
Pancreatic Islets Of Langerhans

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The β-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the α-cells while δ-cells secrete somatostatin that via paracrine mechanisms regulates the α- and β-cell activity. These three peptide hormones are packed into secretory granules that are released through exocytosis following a local increase in intracellular Ca2+ concentration. The high voltage-gated Ca2+ channels (HVCCs) occupy a central role in pancreatic hormone release both as a source of Ca2+ required for excitation-secretion coupling as well as a scaffold for the release machinery. HVCCs are multi-protein complexes composed of the main pore-forming transmembrane α1 and the auxiliary intracellular β, extracellular α2δ, and transmembrane γ subunits. Here, we review the current understanding regarding the role of all HVCC subunits expressed in pancreatic β-cell on electrical activity, excitation-secretion coupling, and β-cell mass. The evidence we review was obtained from many seminal studies employing pharmacological approaches as well as genetically modified mouse models. The significance for diabetes in humans is discussed in the context of genetic variations in the genes encoding for the HVCC subunits.

scholarly journals Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

2012 ◽  
pp. 235-243 ◽  
Author(s):  
Norman Balcazar Morales ◽  
Cecilia Aguilar de Plata
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

scholarly journals Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity

2018 ◽  
Vol 115 (32) ◽  
pp. E7642-E7649 ◽  
Author(s):  
Sandra Kleiner ◽  
Daniel Gomez ◽  
Bezawit Megra ◽  
Erqian Na ◽  
Ramandeep Bhavsar ◽  
...  
Keyword(s):  
Secretory Granules ◽  
Cell Mass ◽  
Loss Of Function ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects ◽  
Pancreatic Islets Of Langerhans ◽  
Normal Body Weight ◽  
Knockin Mouse

SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic β-cell mass. Interestingly, in hyperglycemic conditions induced by the insulin receptor antagonist S961, the R138X mice showed a 50% increase in insulin secretion. This effect was not associated with enhanced β-cell proliferation or mass. Our data suggest that the SLC30A8 R138X LOF mutation may exert beneficial effects on glucose metabolism by increasing the capacity of β-cells to secrete insulin under hyperglycemic conditions.

scholarly journals The redundant role of JAK2 in regulating pancreatic β-cell mass

Islets ◽  
2011 ◽  
Vol 3 (6) ◽  
pp. 389-392 ◽  
Author(s):  
Diana Choi ◽  
Erica P. Cai ◽  
Minna Woo
Keyword(s):  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Redundant Role

scholarly journals Pancreatic β-Cell Protein Granuphilin Binds Rab3 and Munc-18 and Controls Exocytosis

2002 ◽  
Vol 13 (6) ◽  
pp. 1906-1915 ◽  
Author(s):  
Thierry Coppola ◽  
Christian Frantz ◽  
Véronique Perret-Menoud ◽  
Sonia Gattesco ◽  
Harald Hirling ◽  
...  
Keyword(s):  
Binding Protein ◽  
Secretory Granules ◽  
Secretory Vesicle ◽  
Cell Protein ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Protein Receptor

Granuphilin/Slp-4 is a member of the synaptotagmin-like protein family expressed in pancreatic β-cells and in the pituitary gland. We show by confocal microscopy that both granuphilin-a and -b colocalize with insulin-containing secretory granules positioned at the periphery of pancreatic β-cells. Overexpression of granuphilins in insulin-secreting cell lines caused a profound inhibition of stimulus-induced exocytosis. Granuphilins were found to bind to two components of the secretory machinery of pancreatic β-cells, the small GTP-binding protein Rab3 and the solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)–binding protein Munc-18. The interaction with Rab3 occurred only with the GTP-bound form of the protein and was prevented by a point mutation in the effector domain of the GTPase. Structure-function studies using granuphilin-b mutants revealed that complete loss of Rab3 binding is associated with a reduction in the capacity to inhibit exocytosis. However, the granuphilin/Rab3 complex alone is not sufficient to mediate the decrease of exocytosis, suggesting the existence of additional binding partners. Taken together, our observations indicate that granuphilins play an important role in pancreatic β-cell exocytosis. In view of the postulated role of Munc-18 in secretory vesicle docking, our data suggest that granuphilins may also be involved in this process.

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