Esguerra Manuel, Miller Robert F
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Glia. 2002 Sep;39(3):314-9. doi: 10.1002/glia.10115.
Müller cells of the vertebrate retina are prominent radial glia that provide essential support to sustain homeostasis of the tissue, including redistribution of external potassium, uptake and metabolism of neurotransmitters, and secretion of factors that stabilize the retina. Meeting this diversity of functional supports requires that Müller cells express numerous receptors, transporters, enzymes, and tissue factors. In this study, we provide evidence that adds to the dimensions of Müller cell function by demonstrating a unique relationship between external NAD(+) and the mobilization of internal calcium, expressed in the form of calcium waves. The cellular mechanism that supports internal mobilization of calcium appears to depend on a complex multifunctional ectoenzyme, CD38, which converts NAD(+) into the intracellular Ca(2+)-mobilizing second-messenger cyclic ADP-ribose (cADPR) and could function as a detector for extracellular NAD(+), thus providing a novel signal detection system for evaluating the extracellular environment. Our results are consistent with a model of intracellular Ca(2+) mobilization in which membrane-bound CD38 binds extracellular NAD(+) and triggers intracellular Ca(2+) waves either by direct conversion of NAD(+) to cADPR or by activating intracellular cADPR synthesis. Our preliminary results indicate that the Ca(2+) waves induced by external NAD(+) propagate through an internal pathway that depends on the activation of ryanodine receptors, which appear to be distributed throughout the Müller cell cytosol. Because NAD(+) is likely to be enhanced when cells are stress or damaged, CD38 could enable Müller cells to detect NAD(+) under these circumstances and respond appropriately. Alternatively, NAD(+) could also represent a novel extracellular, paracrine function that mediates signaling between glial cells and/or other cellular elements of the retina.
脊椎动物视网膜的穆勒细胞是突出的放射状神经胶质细胞，为维持组织内稳态提供重要支持，包括外部钾离子的重新分布、神经递质的摄取和代谢以及分泌稳定视网膜的因子。要满足这种多样的功能支持，穆勒细胞需要表达众多的受体、转运体、酶和组织因子。在本研究中，我们通过证明外部烟酰胺腺嘌呤二核苷酸（NAD⁺）与以钙波形式表达的细胞内钙动员之间的独特关系，为穆勒细胞功能增添了新的维度。支持细胞内钙动员的细胞机制似乎依赖于一种复杂的多功能胞外酶CD38，它将NAD⁺转化为细胞内钙动员的第二信使环二磷酸腺苷核糖（cADPR），并可能作为细胞外NAD⁺的检测器，从而提供一种用于评估细胞外环境的新型信号检测系统。我们的结果与细胞内钙离子动员模型一致，即膜结合的CD38结合细胞外NAD⁺，并通过将NAD⁺直接转化为cADPR或激活细胞内cADPR合成来触发细胞内钙波。我们的初步结果表明，外部NAD⁺诱导的钙波通过一条依赖于ryanodine受体激活的内部途径传播，ryanodine受体似乎分布在整个穆勒细胞胞质溶胶中。因为当细胞受到应激或损伤时NAD⁺可能会增加，CD38可以使穆勒细胞在这些情况下检测到NAD⁺并做出适当反应。或者，NAD⁺也可能代表一种新型的细胞外旁分泌功能，介导神经胶质细胞和/或视网膜其他细胞成分之间的信号传导。
