The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca2+ dynamics and insulin secretion

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Abstract

Ca2+ signals are central to the stimulation of insulin secretion from pancreatic β-cells by glucose and other agents, including glucagon-like peptide-(GLP-1). Whilst Ca2+ influx through voltage-gated Ca2+ channels on the plasma membrane is a key trigger for glucose-stimulated secretion, mobilisation of Ca2+ from acidic stores has been implicated in the control of more localised Ca2+ changes and membrane potential. Nicotinic acid adenine dinucleotide phosphate (NAADP), generated in β-cells in response to high glucose, is a potent mobiliser of these stores, and has been proposed to act through two pore channels (TPC1 and TPC2, murine gene names Tpcn1 and Tpcn2). Whilst the role of TPC1 in the control of Ca2+ mobilisation and insulin secretion was recently confirmed, conflicting data exist for TPC2. Here, we used the selective and efficient deleter strain, Ins1Cre to achieve β-cell selective deletion of the Tpcn2 gene in mice. βTpcn2 KO mice displayed normal intraperitoneal and oral glucose tolerance, and glucose-stimulated Ca2+ dynamics and insulin secretion from islets were similarly normal. GLP-1-induced Ca2+ increases involved an increase in oscillation frequency from 4.35 to 4.84 per minute (= 0.04) at 8 mM glucose, and this increase was unaffected by the absence of Tpcn2. The current data thus indicate that TPC2 is not absolutely required for normal glucose- or incretin-stimulated insulin secretion from the β-cell. Our findings suggest that TPC1, whose expression tended to increase in Tpcn2 null islets, might be sufficient to support normal Ca2+ dynamics in response to stimulation by nutrients or incretins.

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Cane, M. C., Parrington, J., Rorsman, P., Galione, A., & Rutter, G. A. (2016). The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca2+ dynamics and insulin secretion. Cell Calcium, 59(1), 32–40. https://doi.org/10.1016/j.ceca.2015.12.004

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