Hyperglycemia induces early upregulation of the calcium sensor KChIP3/DREAM/calsenilin in the rat retina

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• 作者：Erika Chavira-Suá ; rez^a ; Alejandro Sandoval^b ; Heberto Quintero^a ; Prisca Bustamante^a ; Ricardo Felix^c ; Mó ; nica Lamas^a ; ^{mlamas@cinvestav.mx}
• 关键词：KChIP3/DREAM/calsenilin ; Retina ; Hyperglycemia ; KV4 channels ; Diabetic retinopathy
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：10 February 2012
• 年：2012
• 卷：418
• 期：2
• 页码：420-425
• 全文大小：804 K

文摘

Hyperglycemia alters the tight control of intracellular calcium dynamics in retinal cells and may lead to the development of diabetic retinopathy. The potassium channel interacting protein 3 (KChIP3) also known as DREAM (Downstream Regulatory Element Antagonist Modulator) or calsenilin (KChIP3/DREAM/calsenilin), a member of the neuronal calcium sensor protein family, is expressed in M¨¹ller glial cells and upregulated under high glucose experimental culture conditions. Here, we analyzed the expression and function of KChIP3 in the retina of streptozotocin induced diabetic Long Evans rats by immunofluorescence confocal microscopy, western blot, co-immunoprecipitation, whole cell patch clamp recording on isolated cells and KChIP3 gene silencing by RNA interference. Three weeks after streptozotocin application, KChIP3 was increased throughout the different retinal layers and this process was not linked to augmented apoptosis. KChIP3 co-immunoprecipitated with voltage gated K⁺ channels of the K_V4.2-4.3 subtype in retinal extracts from control and hyperglycemic rats. Electrophysiological analysis showed that control cells did not express A type (K_V4-mediated) K⁺ currents but most of the cells from streptozotocin treated retinas displayed macroscopic currents with an inactivating component sensitive to 4-AP, suggesting the persistence of the A type currents at early times after treatment. siRNA analysis in M¨¹ller cells cultures grown under high glucose experimental conditions corroborated that, when the expression of KChIP3 is 50 % reduced, the number of cells expressing A type currents decreases significantly. Together these data suggest an altered expression and function of KChIP3 after streptozotocin induced hyperglycemia that might help explain some pathological alterations in early diabetic retinopathy.