Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, suite 3304, 333 Cassell Drive, Baltimore, MD 21224, USA.
Trends Pharmacol Sci. 2010 Dec;31(12):557-66. doi: 10.1016/j.tips.2010.08.007. Epub 2010 Oct 1.
Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)-mitochondrion signaling affects intramitochondrial calcium (Ca(2+)) homeostasis and cellular bioenergetics. ER-nucleus signaling attenuates ER stress. ER-plasma membrane signaling regulates cytosolic Ca(2+) homeostasis and ER-mitochondrion-plasma membrane signaling regulates hippocampal dendritic spine formation. Here, we propose that the sigma-1 receptor (Sig-1R), an ER chaperone protein, acts as an inter-organelle signaling modulator. Sig-1Rs normally reside at the ER-mitochondrion contact called the MAM (mitochondrion-associated ER membrane), where Sig-1Rs regulate ER-mitochondrion signaling and ER-nucleus crosstalk. When cells are stimulated by ligands or undergo prolonged stress, Sig-1Rs translocate from the MAM to the ER reticular network and plasmalemma/plasma membrane to regulate a variety of functional proteins, including ion channels, receptors and kinases. Thus, the Sig-1R serves as an inter-organelle signaling modulator locally at the MAM and remotely at the plasmalemma/plasma membrane. Many pharmacological/physiological effects of Sig-1Rs might relate to this unique action of Sig-1Rs.
细胞器间信号传递在许多生理功能中发挥着重要作用。内质网（ER）-线粒体信号传递影响线粒体内部钙离子（Ca(2+)）稳态和细胞生物能量学。ER-核信号传递可减轻 ER 应激。ER-质膜信号传递调节细胞质 Ca(2+)稳态，ER-线粒体-质膜信号传递调节海马树突棘形成。在这里，我们提出内质网伴侣蛋白 sigma-1 受体（Sig-1R）作为一种细胞器间信号传递调节剂。Sig-1Rs 通常位于内质网-线粒体接触部位，称为 MAM（线粒体相关内质网膜），在该处 Sig-1Rs 调节 ER-线粒体信号传递和 ER-核串扰。当细胞受到配体刺激或经历长期应激时，Sig-1Rs 从 MAM 易位到内质网网状网络和质膜/质膜，以调节多种功能蛋白，包括离子通道、受体和激酶。因此，Sig-1R 作为一种细胞器间信号传递调节剂，在 MAM 处具有局部作用，在质膜/质膜处具有远程作用。Sig-1Rs 的许多药理学/生理学效应可能与 Sig-1Rs 的这种独特作用有关。
