¦Ì-Calpain-mediated deregulation of cardiac, brain, and kidney NCX1 splice variants

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• 作者：Mark Hnatowich ; Hoa Dinh Le ; Danielle DeMoissac ; Kristy Ranson ; Vladimir Yurkov ; James S.C. Gilchrist ; Alexander Omelchenko ; Larry V. Hryshko ; ^{lhryshko@sbrc.ca}
• 关键词：Sodium&ndash ; calcium exchange ; Calpain ; Regulation
• 刊名：Cell Calcium
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：51
• 期：2
• 页码：164-170
• 全文大小：921 K

文摘

¦Ì-Calpain is a Ca²⁺-activated protease abundant in mammalian tissues. Here, we examined the effects of ¦Ì-calpain on three alternatively spliced variants of NCX1 using the giant, excised patch technique. Membrane patches from Xenopus oocytes expressing either heart (NCX1.1), kidney (NCX1.3), or brain (NCX1.4) variants of NCX1 were exposed to ¦Ì-calpain and their Na⁺-dependent (I₁) and Ca²⁺-dependent (I₂) regulatory phenotypes were assessed. For these exchangers, I₁ inactivation is evident as a Na⁺_i-dependent decay of peak outward currents whereas I₂ regulation manifests as outward current activation by micromolar Ca²⁺_i concentrations. Notably, with NCX1.1 and NCX1.4 but not in NCX1.3, higher Ca²⁺_i levels alleviate I₁ inactivation. Our results show that (i) ¦Ì-calpain selectively ablates Ca²⁺-dependent (I₂) regulation leading to a constitutive activation of exchange current, (ii) ¦Ì-calpain has much smaller effects on Na⁺-dependent (I₁) regulation, produced by a slight destabilization of the I₁ state, and (iii) Ca²⁺-dependent regulation (I₂) and Ca²⁺-mediated alleviation of I₁ appear to be functionally distinct mechanisms, the latter of which is left largely intact after ¦Ì-calpain treatment. The ability of ¦Ì-calpain to selectively and constitutively activate Na⁺-Ca²⁺ exchange currents may have important pathophysiological implications in tissue where these splice variants are expressed.