title: The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca²⁺ dynamics and insulin secretion.
abstract: Ca(2+) signals are central to the stimulation of insulin secretion from pancreatic β-cells by glucose and other agents, including glucagon-like peptide-1 (GLP-1). Whilst Ca(2+) influx through voltage-gated Ca(2+) channels on the plasma membrane is a key trigger for glucose-stimulated secretion, mobilisation of Ca(2+) from acidic stores has been implicated in the control of more localised Ca(2+) 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 Ca(2+) 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 Ca(2+) dynamics and insulin secretion from islets were similarly normal. GLP-1-induced Ca(2+) increases involved an increase in oscillation frequency from 4.35 to 4.84 per minute (p=0.04) at 8mM 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 Ca(2+) dynamics in response to stimulation by nutrients or incretins.
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, Du Cane Road, W12 0NN London, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Parrington
authors.affiliation: The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, Du Cane Road, W12 0NN London, UK. Electronic address: g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; D015220:Calcium Channels; D007328:Insulin; C546785:TPCN2 protein, mouse; D002118:Calcium
keywords: Calcium; Diabetes; GLP-1; NAADP; TPC2; β-Cell