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ER-Luminal [Ca ] Regulation of Insp3 Receptor Gating Mediated by an ER

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ER-Luminal [Ca ] Regulation of Insp3 Receptor Gating Mediated by an ER RESEARCH ARTICLE 2+ ER-luminal [Ca ] regulation of InsP3 receptor gating mediated by an ER- luminal peripheral Ca2+-binding protein Horia Vais1, Min Wang1, Karthik Mallilankaraman1, Riley Payne1, Chris McKennan2, Jeffrey T Lock3, Lynn A Spruce4, Carly Fiest1, Matthew Yan-lok Chan1, Ian Parker3,5, Steven H Seeholzer4, J Kevin Foskett1,6*, Don-On Daniel Mak1* 1Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 2Department of Statistics, University of Pittsburgh, Pittsburgh, United States; 3Department of Neurobiology and Behavior, University of California, Irvine, United States; 4Proteomics Core Facility, The Children’s Hospital of Philadelphia, Philadelphia, United States; 5Department of Physiology and Biophysics, University of California, Irvine, United States; 6Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States 2+ 2+ Abstract Modulating cytoplasmic Ca concentration ([Ca ]i) by endoplasmic reticulum (ER)- 2+ localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca -release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding 2+ regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca 2+ concentration ([Ca ]ER) is poorly understood and controversial. We discovered that the InsP3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the 2+ 2+ *For correspondence: channel in the presence of high, physiological [Ca ]ER. The widely-expressed Ca -binding protein [email protected] annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a 2+ (JKF); luminal region of the channel, can modify high-[Ca ]ER inhibition of InsP3R activity. Genetic [email protected] (D-ODM) 2+ knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca 2+ Competing interests: The signaling events. Thus, [Ca ]ER is a major regulator of InsP3R channel activity and InsP3R-mediated 2+ authors declare that no [Ca ]i signaling in cells by controlling an interaction of the channel with a peripheral membrane- competing interests exist. associated Ca2+-binding protein, likely ANXA1. Funding: See page 29 Received: 12 November 2019 Accepted: 15 May 2020 Published: 18 May 2020 Introduction Modulating cytoplasmic free Ca2+ concentration ([Ca2+] ) is a universal signaling pathway that regu- Reviewing editor: Mark T i Nelson, University of Vermont, lates numerous cell-physiological processes (Berridge, 2016). Ubiquitous endoplasmic reticulum 2+ United States (ER)-localized inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) Ca -release channels play a cen- tral role in this pathway (Foskett et al., 2007). InsP3 generated in response to extracellular stimuli Copyright Vais et al. This 2+ binds to and activates InsP3R channels to release Ca stored in the ER lumen, generating diverse article is distributed under the 2+ local and global [Ca ]i signals (Berridge, 2016). Whereas much is known regarding regulation of terms of the Creative Commons 2+ Attribution License, which InsP3R channel gating by multiple processes, including binding of cytoplasmic ligands (Ca , InsP3 4– permits unrestricted use and and ATP ), post-translational modifications, interactions with proteins, clustering and differential 2+ redistribution provided that the localization (Berridge, 2016), the regulation of InsP3R channel activity by Ca concentration in the 2+ original author and source are ER lumen ([Ca ]ER) is poorly understood and controversial (see (Caroppo et al., 2003; Yamasaki- 2+ credited. Mann and Parker, 2011) and references therein). InsP3R activity influences [Ca ]ER, which is critical Vais et al. eLife 2020;9:e53531. DOI: https://doi.org/10.7554/eLife.53531 1 of 32 Research article Structural Biology and Molecular Biophysics for many processes, including regulation of bioenergetics, protein biogenesis and folding, and Ca2+ 2+ signaling (Corbett and Michalak, 2000). [Ca ]ER dysregulation is associated with pathological con- ditions, including ER stress responses, diabetes, cardiac dysfunction, neurodegeneration, defective cell proliferation and cell death (Berridge, 2016). Mechanisms that link cellular processes with 2+ 2+ [Ca ]ER, and the connections between [Ca ]ER dysregulation and disease pathogenesis are ill- defined and poorly understood (Mekahli et al., 2011). 2+ For a long time, regulation of InsP3R channel activity by [Ca ]ER has primarily been examined by 2+ 2+ approaches that relied on changes in [Ca ]i or [Ca ]ER to infer channel activity (Caroppo et al., 2003; Yamasaki-Mann and Parker, 2011) and references therein), with no rigorous control of both 2+ 2+ [Ca ]ER and [Ca ]i simultaneously. It has therefore been difficult to differentiate feed-through 2+ 2+ 2+ effects in which Ca flux through channel raises [Ca ]i at the cytoplasmic Ca -binding sites to 2+ modulate channel activity from direct effects of [Ca ]ER on the luminal aspect of the InsP3R. Patch- clamp electrophysiology allows rigorous, simultaneous control of [Ca2+] on both sides of the mem- brane, but intracellular ER membranes are not accessible to patch pipettes. To overcome this limita- tion, we made use of the fact that the ER membrane is continuous with the outer nuclear membrane (Dingwall and Laskey, 1992) and pioneered the use of nuclear patch-clamp electrophysiology on isolated nuclei (Mak et al., 2005). This enables the activities of single InsP3R channels to be recorded in their native ER membrane and luminal milieus. Different patch-clamp configurations 2+ 2+ have been used to study single InsP3R channels under rigorously controlled [Ca ]ER and [Ca ]i: including on-nucleus (on-nuc, cytoplasmic aspect of the channel faces into the pipette solution with the luminal milieu intact, Figure 1A), excised luminal-side-out (lum-out, cytoplasmic aspect of the channel faces into the pipette solution with the luminal aspect exposed to the bath solution, Figure 1B) and excised cytoplasmic-side-out (cyto-out, cytoplasmic aspect of the channel perfused by the bath solution with the luminal aspect facing the pipette solution, Figure 1C; Mak et al., 2+ + 2013a; Mak et al., 2013b). Because of the relatively low selectivity of InsP3R channels for Ca vs K (15.2 : 1 [Vais et al., 2010a]) and orders of magnitude higher [K+] (140 mM) than that of other ions 2+ in the physiological solutions used in our experiments (70 nM to 600 mM [Ca ]free; 0 or 200 mM 2+ + [Mg ]free), the electrical currents through open InsP3R channels are overwhelmingly carried by K in all our patch-clamp electrophysiology experiments, enabling the kinetics of channel gating to be studied with both luminal and cytoplasmic [Ca2+] well-defined and controlled. Using the nuclear patch-clamp approach in a previous study (Vais et al., 2012), we demonstrated 2+ 2+ that InsP3R channel activity can be modulated by [Ca ]ER indirectly via feed-through effects of Ca 2+ 2+ flux driven through an open channel by high [Ca ]ER that raises the local [Ca ]i in the channel vicin- ity to regulate its activity through its cytoplasmic activating and inhibitory Ca2+-binding sites (Figure 2A). That study demonstrated that these feed-through effects can be completely abrogated 2+ 2+ 2+ by sufficient Ca chelation on the cytoplasmic side to buffer local [Ca ]i at cytoplasmic Ca Figure 1. Schematic diagram illustrating the orientation of InsP3R channels in isolated nuclear membrane patches and InsP3-containing solution relative to the micropipette in various configurations of nuclear patch-clamping. (A) On-nucleus configuration with outer nuclear membrane intact, (B) excised luminal-side-out configuration, (C) excised cytoplasmic-side-out configuration. Vais et al. eLife 2020;9:e53531. DOI: https://doi.org/10.7554/eLife.53531 2 of 32 Research article Structural Biology and Molecular Biophysics 2+ 2+ 2+ Figure 2. Possible mechanisms of [Ca ]ER regulation of InsP3R channel activity. (A) Ca flux through an open InsP3R channel driven by high [Ca ]ER 2+ 2+ 2+ raises local [Ca ]i in the pore vicinity to regulate the channel through its cytoplasmic activating and inhibitory Ca -binding sites. (B) Ca binds directly to an intrinsic site on the luminal side of the channel to regulate its activity. (C) Ca2+ binding to a peripheral protein in the ER lumen regulates channel activity indirectly, by promoting interaction of the peripheral protein with the InsP3R. 2+ binding sites of the InsP3R. In the presence of 5 mM 5,5’-diBromo BAPTA (a fast acting Ca chela- tor) on the cytoplasmic side in the lum-out excised patch configuration (Figure 1B), the open proba- 2+ bility Po of the InsP3R channel did not change discernably when the [Ca ]ER was switched between 70 nM and 300 mM, no matter whether saturating 10 mM [InsP3] (Figure 2C in Vais et al., 2012) or sub-saturating 3 mM [InsP3] (Figure 7B in Vais et al., 2012) was present in the micropipette (2 mM 2+ 2+ [Ca ]i was in the micropipette in all experiments described here). Thus, as long as [Ca ]free on the 2+ cytoplasmic side was well buffered, switching [Ca ]ER between 70 nM and 300 mM in lum-out excised membrane patches had no effect on channel activity. This definitively ruled out the possibil- 2+ ity that InsP3R activity is modulated directly by an intrinsic Ca -regulatory site on the luminal side that is either part of the InsP3R or of a protein that constitutively interacts with the channel (Figure 2B). Notably, however, in all previous studies of InsP3R channel gating, nuclei were isolated into a 2+ 2+ bath solution with low [Ca ]free to simulate physiological resting [Ca ]i (Mak and Foskett, 2015). Although sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is present in the nuclear envelope (Lanini et al., 1992), the bath solutions contained no MgATP to energize it. Thus, passive Ca2+ leaks 2+ 2+ equilibrated [Ca ]free in the perinuclear space of the isolated nuclei (effectively [Ca ]ER) with bath 2+ 2+ [Ca ] at unphysiologically low levels.
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