DOI: 10.1073/pnas.95.26.15821. Inositol 1,4,5-tris-phosphate activation of inositol tris-phosphate receptor Ca <sup>2+</sup> channel by ligand tuning of Ca <sup>2+</sup> inhibition [Penn]

Inositol 1,4,5-tris-phosphate activation of inositol tris-phosphate receptor Ca 2+ channel by ligand tuning of Ca 2+ inhibition

10.1073/pnas.95.26.15821

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Inositol 1,4,5-tris-phosphate (IP 3 ) binding to its receptors (IP 3 R) in the endoplasmic reticulum (ER) activates Ca 2+ release from the ER lumen to the cytoplasm, generating complex cytoplasmic Ca 2+ concentration signals including temporal oscillations and propagating waves. IP 3 -mediated Ca 2+ release is also controlled by cytoplasmic Ca 2+ concentration with both positive and negative feedback. Single-channel properties of the IP 3 R in its native ER membrane were investigated by patch clamp electrophysiology of isolated Xenopus oocyte nuclei to determine the dependencies of IP 3 R on cytoplasmic Ca 2+ and IP 3 concentrations under rigorously defined conditions. Instead of the expected narrow bell-shaped cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) response centered at ≈300 nM–1 μM, the open probability remained elevated (≈0.8) in the presence of saturating levels (10 μM) of IP 3 , even as [Ca 2+ ] i was raised to high concentrations, displaying two distinct types of functional Ca 2+ binding sites: activating sites with half-maximal activating [Ca 2+ ] i ( K act ) of 210 nM and Hill coefficient ( H act ) ≈2; and inhibitory sites with half-maximal inhibitory [Ca 2+ ] i ( K inh ) of 54 μM and Hill coefficient ( H inh ) ≈4. Lowering IP 3 concentration was without effect on Ca 2+ activation parameters or H inh , but decreased K inh with a functional half-maximal activating IP 3 concentration ( K IP 3 ) of 50 nM and Hill coefficient ( H IP 3 ) of 4 for IP 3 . These results demonstrate that Ca 2+ is a true receptor agonist, whereas the sole function of IP 3 is to relieve Ca 2+ inhibition of IP 3 R. Allosteric tuning of Ca 2+ inhibition by IP 3 enables the individual IP 3 R Ca 2+ channel to respond in a graded fashion, which has implications for localized and global cytoplasmic Ca 2+ concentration signaling and quantal Ca 2+ release.

Bibliography

Mak, D.-O. D., McBride, S., & Foskett, J. K. (1998). Inositol 1,4,5-tris-phosphate activation of inositol tris-phosphate receptor Ca 2+ channel by ligand tuning of Ca 2+ inhibition. Proceedings of the National Academy of Sciences, 95(26), 15821â15825.

Authors 3

Don-On Daniel Mak (first)
Sean McBride (additional)
J. Kevin Foskett (additional)

References 38 Referenced 242

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:40 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:10 p.m.)
Indexed	14 minutes ago (Aug. 29, 2025, 6:22 a.m.)
Issued	26 years, 8 months ago (Dec. 22, 1998)
Published	26 years, 8 months ago (Dec. 22, 1998)
Published Online	26 years, 8 months ago (Dec. 22, 1998)
Published Print	26 years, 8 months ago (Dec. 22, 1998)

Funders 0

None

BibTeX

@article{Mak_1998, title={Inositol 1,4,5-tris-phosphate activation of inositol tris-phosphate receptor Ca 2+ channel by ligand tuning of Ca 2+ inhibition}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.26.15821}, DOI={10.1073/pnas.95.26.15821}, number={26}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Mak, Don-On Daniel and McBride, Sean and Foskett, J. Kevin}, year={1998}, month=dec, pages={15821–15825} }

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  "abstract": "<jats:p>\n            Inositol 1,4,5-tris-phosphate (IP\n            <jats:sub>3</jats:sub>\n            ) binding to its receptors (IP\n            <jats:sub>3</jats:sub>\n            R) in the endoplasmic reticulum (ER) activates Ca\n            <jats:sup>2+</jats:sup>\n            release from the ER lumen to the cytoplasm, generating complex cytoplasmic Ca\n            <jats:sup>2+</jats:sup>\n            concentration signals including temporal oscillations and propagating waves. IP\n            <jats:sub>3</jats:sub>\n            -mediated Ca\n            <jats:sup>2+</jats:sup>\n            release is also controlled by cytoplasmic Ca\n            <jats:sup>2+</jats:sup>\n            concentration with both positive and negative feedback. Single-channel properties of the IP\n            <jats:sub>3</jats:sub>\n            R in its native ER membrane were investigated by patch clamp electrophysiology of isolated\n            <jats:italic>Xenopus</jats:italic>\n            oocyte nuclei to determine the dependencies of IP\n            <jats:sub>3</jats:sub>\n            R on cytoplasmic Ca\n            <jats:sup>2+</jats:sup>\n            and IP\n            <jats:sub>3</jats:sub>\n            concentrations under rigorously defined conditions. Instead of the expected narrow bell-shaped cytoplasmic free Ca\n            <jats:sup>2+</jats:sup>\n            concentration ([Ca\n            <jats:sup>2+</jats:sup>\n            ]\n            <jats:sub>i</jats:sub>\n            ) response centered at \u2248300 nM\u20131 \u03bcM, the open probability remained elevated (\u22480.8) in the presence of saturating levels (10 \u03bcM) of IP\n            <jats:sub>3</jats:sub>\n            , even as [Ca\n            <jats:sup>2+</jats:sup>\n            ]\n            <jats:sub>i</jats:sub>\n            was raised to high concentrations, displaying two distinct types of functional Ca\n            <jats:sup>2+</jats:sup>\n            binding sites: activating sites with half-maximal activating [Ca\n            <jats:sup>2+</jats:sup>\n            ]\n            <jats:sub>i</jats:sub>\n            (\n            <jats:italic>K</jats:italic>\n            <jats:sub>act</jats:sub>\n            ) of 210 nM and Hill coefficient (\n            <jats:italic>H</jats:italic>\n            <jats:sub>act</jats:sub>\n            ) \u22482; and inhibitory sites with half-maximal inhibitory [Ca\n            <jats:sup>2+</jats:sup>\n            ]\n            <jats:sub>i</jats:sub>\n            (\n            <jats:italic>K</jats:italic>\n            <jats:sub>inh</jats:sub>\n            ) of 54 \u03bcM and Hill coefficient (\n            <jats:italic>H</jats:italic>\n            <jats:sub>inh</jats:sub>\n            ) \u22484. Lowering IP\n            <jats:sub>3</jats:sub>\n            concentration was without effect on Ca\n            <jats:sup>2+</jats:sup>\n            activation parameters or\n            <jats:italic>H</jats:italic>\n            <jats:sub>inh</jats:sub>\n            , but decreased\n            <jats:italic>K</jats:italic>\n            <jats:sub>inh</jats:sub>\n            with a functional half-maximal activating IP\n            <jats:sub>3</jats:sub>\n            concentration (\n            <jats:italic>K</jats:italic>\n            <jats:sub>\n              IP\n              <jats:sub>3</jats:sub>\n            </jats:sub>\n            ) of 50 nM and Hill coefficient (\n            <jats:italic>H</jats:italic>\n            <jats:sub>\n              IP\n              <jats:sub>3</jats:sub>\n            </jats:sub>\n            ) of 4 for IP\n            <jats:sub>3</jats:sub>\n            . These results demonstrate that Ca\n            <jats:sup>2+</jats:sup>\n            is a true receptor agonist, whereas the sole function of IP\n            <jats:sub>3</jats:sub>\n            is to relieve Ca\n            <jats:sup>2+</jats:sup>\n            inhibition of IP\n            <jats:sub>3</jats:sub>\n            R. Allosteric tuning of Ca\n            <jats:sup>2+</jats:sup>\n            inhibition by IP\n            <jats:sub>3</jats:sub>\n            enables the individual IP\n            <jats:sub>3</jats:sub>\n            R Ca\n            <jats:sup>2+</jats:sup>\n            channel to respond in a graded fashion, which has implications for localized and global cytoplasmic Ca\n            <jats:sup>2+</jats:sup>\n            concentration signaling and quantal Ca\n            <jats:sup>2+</jats:sup>\n            release.\n          </jats:p>",
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