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Sensory neurons derived from diabetic rats have diminished internal Ca2+ stores linked to impaired re-uptake by the endoplasmic reticulum

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Author(s): Elena Zherebitskaya | Jason Schapansky | Eli Akude | Darrell R Smith | Randy Van der Ploeg | Natasha Solovyova | Alexei Verkhratsky | Paul Fernyhough

Journal: ASN Neuro
ISSN 1759-0914

Volume: 4;
Issue: 1;
Start page: e00072;
Date: 2012;
Original page

Keywords: axon plasticity | diabetic neuropathy | dorsal root ganglia (DRG) | neurodegeneration | sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)

ABSTRACT
Distal symmetrical sensory neuropathy in diabetes involves the dying back of axons, and the pathology equates with axonal dystrophy generated under conditions of aberrant Ca2+ signalling. Previous work has described abnormalities in Ca2+ homoeostasis in sensory and dorsal horn neurons acutely isolated from diabetic rodents. We extended this work by testing the hypothesis that sensory neurons exposed to long-term Type 1 diabetes in vivo would exhibit abnormal axonal Ca2+ homoeostasis and focused on the role of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase). DRG (dorsal root ganglia) sensory neurons from age-matched normal and 3–5-month-old STZ (streptozotocin)-diabetic rats (an experimental model of Type 1 diabetes) were cultured. At 1–2 days in vitro an array of parameters were measured to investigate Ca2+ homoeostasis including (i) axonal levels of intracellular Ca2+, (ii) Ca2+ uptake by the ER (endoplasmic reticulum), (iii) assessment of Ca2+ signalling following a long-term thapsigargin-induced blockade of SERCA and (iv) determination of expression of ER mass and stress markers using immunocytochemistry and Western blotting. KCl- and caffeine-induced Ca2+ transients in axons were 2-fold lower in cultures of diabetic neurons compared with normal neurons indicative of reduced ER calcium loading. The rate of uptake of Ca2+ into the ER was reduced by 2-fold (P
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