Electrical Signals in the ER Are Cell Type and Stimulus Specific with Extreme Spatial Compartmentalization in Neurons

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Jan 14

PMID 36640310

Authors

Evan P Campbell

Ahmed A Abushawish

Lauren A Valdez

Miriam K Bell

Melita Haryono

Padmini Rangamani

Brenda L Bloodgood

Affiliations

Soon will be listed here.

Abstract

The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.

Citing Articles

Evolution, classification, and mechanisms of transport, activity regulation, and substrate specificity of ZIP metal transporters.

Hu J, Jiang Y Crit Rev Biochem Mol Biol. 2024; 59(5):245-266.

PMID: 39431645 PMC: 11658277. DOI: 10.1080/10409238.2024.2405476.

Dimerization is required for the glycosylation of S1-S2 linker of sea urchin voltage-gated proton channel Hv1.

Okochi Y, Jinno Y, Okamura Y Biophys J. 2024; 123(24):4221-4232.

PMID: 39086135 PMC: 11700361. DOI: 10.1016/j.bpj.2024.07.034.

Calcium channel signalling at neuronal endoplasmic reticulum-plasma membrane junctions.

Maciag F, Chhikara A, Heine M Biochem Soc Trans. 2024; 52(4):1617-1629.

PMID: 38934485 PMC: 11668288. DOI: 10.1042/BST20230819.

Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca signals.

Crapart C, Scott Z, Konno T, Sharma A, Parutto P, Bailey D Proc Natl Acad Sci U S A. 2024; 121(13):e2312172121.

PMID: 38502705 PMC: 10990089. DOI: 10.1073/pnas.2312172121.

How neurons maintain their axons long-term: an integrated view of axon biology and pathology.

Smith G, Sweeney S, OKane C, Prokop A Front Neurosci. 2023; 17:1236815.

PMID: 37564364 PMC: 10410161. DOI: 10.3389/fnins.2023.1236815.

References

Pivovarova N, Leapman R, Buchanan R, Reese T, Andrews S . Activity-dependent calcium sequestration in dendrites of hippocampal neurons in brain slices. J Neurosci. 1997; 17(22):8729-38. PMC: 6573076. View

Holbro N, Grunditz A, Oertner T . Differential distribution of endoplasmic reticulum controls metabotropic signaling and plasticity at hippocampal synapses. Proc Natl Acad Sci U S A. 2009; 106(35):15055-60. PMC: 2736455. DOI: 10.1073/pnas.0905110106. View

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T . Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7):676-82. PMC: 3855844. DOI: 10.1038/nmeth.2019. View

Kawano S, Nakamura F, Tanaka T, Hiraoka M . Cardiac sarcoplasmic reticulum chloride channels regulated by protein kinase A. Circ Res. 1992; 71(3):585-9. DOI: 10.1161/01.res.71.3.585. View

Chamberland S, Yang H, Pan M, Evans S, Guan S, Chavarha M . Fast two-photon imaging of subcellular voltage dynamics in neuronal tissue with genetically encoded indicators. Elife. 2017; 6. PMC: 5584994. DOI: 10.7554/eLife.25690. View

Buyse G, Trouet D, Voets T, Missiaen L, Droogmans G, Nilius B . Evidence for the intracellular location of chloride channel (ClC)-type proteins: co-localization of ClC-6a and ClC-6c with the sarco/endoplasmic-reticulum Ca2+ pump SERCA2b. Biochem J. 1998; 330 ( Pt 2):1015-21. PMC: 1219239. DOI: 10.1042/bj3301015. View

Andersson H, Kappeler F, Hauri H . Protein targeting to endoplasmic reticulum by dilysine signals involves direct retention in addition to retrieval. J Biol Chem. 1999; 274(21):15080-4. DOI: 10.1074/jbc.274.21.15080. View

Li B, Jie W, Huang L, Wei P, Li S, Luo Z . Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling. Nat Neurosci. 2014; 17(8):1055-63. PMC: 4115017. DOI: 10.1038/nn.3744. View

Villette V, Chavarha M, Dimov I, Bradley J, Pradhan L, Mathieu B . Ultrafast Two-Photon Imaging of a High-Gain Voltage Indicator in Awake Behaving Mice. Cell. 2019; 179(7):1590-1608.e23. PMC: 6941988. DOI: 10.1016/j.cell.2019.11.004. View

10.

Gao C, Cai Y, Wang Y, Kang B, Aniento F, Robinson D . Retention mechanisms for ER and Golgi membrane proteins. Trends Plant Sci. 2014; 19(8):508-15. DOI: 10.1016/j.tplants.2014.04.004. View

11.

Vierra N, Kirmiz M, van der List D, Santana L, Trimmer J . Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons. Elife. 2019; 8. PMC: 6839919. DOI: 10.7554/eLife.49953. View

12.

Spacek J, Harris K . Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci. 1997; 17(1):190-203. PMC: 6793680. View

13.

Reiner A, Levitz J . Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert. Neuron. 2018; 98(6):1080-1098. PMC: 6484838. DOI: 10.1016/j.neuron.2018.05.018. View

14.

Saminathan A, Devany J, Veetil A, Suresh B, Smitha Pillai K, Schwake M . A DNA-based voltmeter for organelles. Nat Nanotechnol. 2020; 16(1):96-103. PMC: 8513801. DOI: 10.1038/s41565-020-00784-1. View

15.

Thillaiappan N, Chavda A, Tovey S, Prole D, Taylor C . Ca signals initiate at immobile IP receptors adjacent to ER-plasma membrane junctions. Nat Commun. 2017; 8(1):1505. PMC: 5686115. DOI: 10.1038/s41467-017-01644-8. View

16.

Takei K, Stukenbrok H, Metcalf A, Mignery G, Sudhof T, Volpe P . Ca2+ stores in Purkinje neurons: endoplasmic reticulum subcompartments demonstrated by the heterogeneous distribution of the InsP3 receptor, Ca(2+)-ATPase, and calsequestrin. J Neurosci. 1992; 12(2):489-505. PMC: 6575620. View

17.

Dogic D, Dubois A, de Chassey B, Lefkir Y, Letourneur F . ERGIC-53 KKAA signal mediates endoplasmic reticulum retrieval in yeast. Eur J Cell Biol. 2001; 80(2):151-5. DOI: 10.1078/0171-9335-00145. View

18.

Cornejo V, Ofer N, Yuste R . Voltage compartmentalization in dendritic spines in vivo. Science. 2021; 375(6576):82-86. PMC: 8942082. DOI: 10.1126/science.abg0501. View

19.

Wu Y, Whiteus C, Xu C, Hayworth K, Weinberg R, Hess H . Contacts between the endoplasmic reticulum and other membranes in neurons. Proc Natl Acad Sci U S A. 2017; 114(24):E4859-E4867. PMC: 5474793. DOI: 10.1073/pnas.1701078114. View

20.

Walton P, Airey J, Sutko J, Beck C, Mignery G, Sudhof T . Ryanodine and inositol trisphosphate receptors coexist in avian cerebellar Purkinje neurons. J Cell Biol. 1991; 113(5):1145-57. PMC: 2289007. DOI: 10.1083/jcb.113.5.1145. View