CAPS1 and CAPS2 regulate stability and recruitment of insulin granules in mouse pancreatic beta cells.
CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain enigmatic. Here we show that CAPS2(-/-) and CAPS1(+/-);CAPS2(-/-) mice, despite having increased insulin sensitivity, are glucose intolerant and that this effect is attributable to a marked reduction of glucose-induced insulin secretion. This correlates with diminished Ca(2+)-dependent exocytosis, a reduction in the size of the morphologically docked pool, a decrease in the readily releasable pool of secretory vesicles, slowed granule priming, and suppression of second-phase (but not first-phase) insulin secretion. In beta cells of CAPS1(+/-);CAPS2(-/-) mice, the lowered insulin content and granule numbers were associated with an increase in lysosome numbers and lysosomal enzyme activity. We conclude that although CAPS proteins are not required for Ca(2+)-dependent exocytosis to proceed, they exert a modulatory effect on insulin granule priming, exocytosis, and stability.
Speidel
Dina
D
Department of Clinical Sciences Malmö, Lund University, UMAS, Malmö, Sweden. dina.speidel@med.lu.se
Salehi
Albert
A
Obermueller
Stefanie
S
Lundquist
Ingmar
I
Brose
Nils
N
Renström
Erik
E
Rorsman
Patrik
P
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004594:Electrophysiology; D005089:Exocytosis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D007515:Islets of Langerhans / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020799:Pancrelipase / Q000378:metabolism / Q000648:ultrastructure
C480975:CAPS2 protein, mouse; C510820:Cadps protein, mouse; D002135:Calcium-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D020799:Pancrelipase; D002118:Calcium