Photopharmacological modulation of native CRAC channels using azoboronate photoswitches

Ronald Udasin; Anwesha Sil; Elia Zomot; Hadas Achildiev Cohen; Jozafina Haj; Nurit Engelmayer; Shaya Lev; Alexander M. Binshtok; Yuval Shaked; Michael A. Kienzler; Raz Palty

doi:10.1073/pnas.2118160119

Photopharmacological modulation of native CRAC channels using azoboronate photoswitches

Ronald Udasin, Anwesha Sil, Elia Zomot, Hadas Achildiev Cohen, Jozafina Haj, Nurit Engelmayer, Shaya Lev, Alexander M. Binshtok, Yuval Shaked, Michael A. Kienzler^*, Raz Palty^*

^*Corresponding author for this work

Department of Medical Neurobiology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Store-operated calcium entry through calcium release–activated calcium (CRAC) channels replenishes intracellular calcium stores and plays a critical role in cellular calcium signaling. CRAC channels are activated by tightly regulated interaction between the endoplasmic reticulum (ER) calcium sensor STIM proteins and plasma membrane (PM) Orai channels. Our current understanding of the role of STIM–Orai-dependent calcium signals under physiologically relevant conditions remains limited in part due to a lack of spatiotemporally precise methods for direct manipulation of endogenous CRAC channels. Here, we report the synthesis and characterization of azoboronate light-operated CRAC channel inhibitors (LOCIs) that allow for a dynamic and fully reversible remote modulation of the function of native CRAC channels using ultraviolet (UV) and visible light. We demonstrate the use of LOCI-1 to modulate gene expression in T lymphocytes, cancer cell seeding at metastatic sites, and pain-related behavior.

Original language	American English
Article number	e2118160119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	13
DOIs	https://doi.org/10.1073/pnas.2118160119
State	Published - 29 Mar 2022

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This work was supported by grants from the NSF (Grant 2116412 to M.A.K.), the Israeli Science Foundation (Grant 1048/18 to R.P. and Grant 1470/17 to A.M.B.), the Sessile and Seymour Alpert Chair in Pain Research (A.M.B.), the US–Israel Binational Science Foundation (Grant 2019657 to R.P.), and the Rappaport Research Institute (2018 Thematic Grant to R.P. and Y.S.).

Publisher Copyright:
© 2022 the Author(s).

Keywords

CRAC channel
Orai
STIM
azobenzene
photoswitch

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.2118160119

Cite this

Udasin, R., Sil, A., Zomot, E., Cohen, H. A., Haj, J., Engelmayer, N., Lev, S., Binshtok, A. M., Shaked, Y., Kienzler, M. A., & Palty, R. (2022). Photopharmacological modulation of native CRAC channels using azoboronate photoswitches. Proceedings of the National Academy of Sciences of the United States of America, 119(13), Article e2118160119. https://doi.org/10.1073/pnas.2118160119

@article{ca916d0d820547be9660d341538a1cef,

title = "Photopharmacological modulation of native CRAC channels using azoboronate photoswitches",

abstract = "Store-operated calcium entry through calcium release–activated calcium (CRAC) channels replenishes intracellular calcium stores and plays a critical role in cellular calcium signaling. CRAC channels are activated by tightly regulated interaction between the endoplasmic reticulum (ER) calcium sensor STIM proteins and plasma membrane (PM) Orai channels. Our current understanding of the role of STIM–Orai-dependent calcium signals under physiologically relevant conditions remains limited in part due to a lack of spatiotemporally precise methods for direct manipulation of endogenous CRAC channels. Here, we report the synthesis and characterization of azoboronate light-operated CRAC channel inhibitors (LOCIs) that allow for a dynamic and fully reversible remote modulation of the function of native CRAC channels using ultraviolet (UV) and visible light. We demonstrate the use of LOCI-1 to modulate gene expression in T lymphocytes, cancer cell seeding at metastatic sites, and pain-related behavior.",

keywords = "CRAC channel, Orai, STIM, azobenzene, photoswitch",

author = "Ronald Udasin and Anwesha Sil and Elia Zomot and Cohen, {Hadas Achildiev} and Jozafina Haj and Nurit Engelmayer and Shaya Lev and Binshtok, {Alexander M.} and Yuval Shaked and Kienzler, {Michael A.} and Raz Palty",

note = "Funding Information: ACKNOWLEDGMENTS. This work was supported by grants from the NSF (Grant 2116412 to M.A.K.), the Israeli Science Foundation (Grant 1048/18 to R.P. and Grant 1470/17 to A.M.B.), the Sessile and Seymour Alpert Chair in Pain Research (A.M.B.), the US–Israel Binational Science Foundation (Grant 2019657 to R.P.), and the Rappaport Research Institute (2018 Thematic Grant to R.P. and Y.S.). Publisher Copyright: {\textcopyright} 2022 the Author(s).",

year = "2022",

month = mar,

day = "29",

doi = "10.1073/pnas.2118160119",

language = "American English",

volume = "119",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "13",

}

TY - JOUR

T1 - Photopharmacological modulation of native CRAC channels using azoboronate photoswitches

AU - Udasin, Ronald

AU - Sil, Anwesha

AU - Zomot, Elia

AU - Cohen, Hadas Achildiev

AU - Haj, Jozafina

AU - Engelmayer, Nurit

AU - Lev, Shaya

AU - Binshtok, Alexander M.

AU - Shaked, Yuval

AU - Kienzler, Michael A.

AU - Palty, Raz

N1 - Funding Information: ACKNOWLEDGMENTS. This work was supported by grants from the NSF (Grant 2116412 to M.A.K.), the Israeli Science Foundation (Grant 1048/18 to R.P. and Grant 1470/17 to A.M.B.), the Sessile and Seymour Alpert Chair in Pain Research (A.M.B.), the US–Israel Binational Science Foundation (Grant 2019657 to R.P.), and the Rappaport Research Institute (2018 Thematic Grant to R.P. and Y.S.). Publisher Copyright: © 2022 the Author(s).

PY - 2022/3/29

Y1 - 2022/3/29

N2 - Store-operated calcium entry through calcium release–activated calcium (CRAC) channels replenishes intracellular calcium stores and plays a critical role in cellular calcium signaling. CRAC channels are activated by tightly regulated interaction between the endoplasmic reticulum (ER) calcium sensor STIM proteins and plasma membrane (PM) Orai channels. Our current understanding of the role of STIM–Orai-dependent calcium signals under physiologically relevant conditions remains limited in part due to a lack of spatiotemporally precise methods for direct manipulation of endogenous CRAC channels. Here, we report the synthesis and characterization of azoboronate light-operated CRAC channel inhibitors (LOCIs) that allow for a dynamic and fully reversible remote modulation of the function of native CRAC channels using ultraviolet (UV) and visible light. We demonstrate the use of LOCI-1 to modulate gene expression in T lymphocytes, cancer cell seeding at metastatic sites, and pain-related behavior.

AB - Store-operated calcium entry through calcium release–activated calcium (CRAC) channels replenishes intracellular calcium stores and plays a critical role in cellular calcium signaling. CRAC channels are activated by tightly regulated interaction between the endoplasmic reticulum (ER) calcium sensor STIM proteins and plasma membrane (PM) Orai channels. Our current understanding of the role of STIM–Orai-dependent calcium signals under physiologically relevant conditions remains limited in part due to a lack of spatiotemporally precise methods for direct manipulation of endogenous CRAC channels. Here, we report the synthesis and characterization of azoboronate light-operated CRAC channel inhibitors (LOCIs) that allow for a dynamic and fully reversible remote modulation of the function of native CRAC channels using ultraviolet (UV) and visible light. We demonstrate the use of LOCI-1 to modulate gene expression in T lymphocytes, cancer cell seeding at metastatic sites, and pain-related behavior.

KW - CRAC channel

KW - Orai

KW - STIM

KW - azobenzene

KW - photoswitch

UR - http://www.scopus.com/inward/record.url?scp=85126873090&partnerID=8YFLogxK

U2 - 10.1073/pnas.2118160119

DO - 10.1073/pnas.2118160119

M3 - Article

C2 - 35312368

AN - SCOPUS:85126873090

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 13

M1 - e2118160119

ER -

Photopharmacological modulation of native CRAC channels using azoboronate photoswitches

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this