The oxytocin signaling complex reveals a molecular switch for cation dependence

Meyerowitz, Justin; Robertson, Michael J.; Barros-Álvarez, Ximena; Panova, Ouliana; Nwokonko, Robert M.; Gao, Yang; Skiniotis, Georgios

doi:10.1038/s41594-022-00728-4

Cited by 34 publications

(60 citation statements)

References 66 publications

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“…Interestingly, OT-OTR binding did not reach maximal efficacy at physiologically relevant Mg 2+ concentrations. These results are consistent with previous findings that demonstrated that, in the complete absence of Mg 2+ , OT only reaches approximately 50% of its maximal efficacy (Meyerowitz et al, 2022). Consistent with these findings, while OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, and the addition of a supraphysiological (1.75mM) concentration of Mg 2+ significantly enhanced this effect, implying a supportive impact of Mg 2+ on OT craniofacial analgesia.…”

Section: Discussionsupporting

confidence: 92%

“…The requirement of Mg 2+ for OT's high affinity for its receptor has long been known (Antoni & Chadio, 1989). More recently, the precise architecture of this Mg 2+ coordination site has been elucidated in the high-resolution cryo-electron microscopy structure of OT bound to its receptor, revealing that OT and OTR together form an octahedral Mg 2+ coordination site between receptor and ligand (Meyerowitz et al, 2022). However, the functional consequence of Mg 2+ control of OT binding has not been adequately examined, particularly with regard to how Mg 2+ levels could affect the impact of OT-OTR binding on pain as well as other phenomena.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these results of these three sets of experiments suggest that Mg 2+ is required for full agonism of OT and that, for pain and in many other therapeutic or disease settings, the efficacy of OT may be limited by the availability of Mg 2+ . Thus, the addition of Mg 2+ to OT formulations or the development of novel OT analogs based on recently elucidated OTR structural biology (Meyerowitz et al, 2022) that obviate the need for Mg 2+ may enable enhanced OTR efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…The last of these, OTR affinity, is closely modulated by the local concentration of magnesium cation (Mg 2+ ) which acts as an essential cofactor dramatically increasing the affinity of OTR for OT (Antoni & Chadio, 1989;Bharadwaj, Porreca, et al, 2021;Gimpl, Reitz, Brauer, & Trossen, 2008). Figure 1 shows the recently published structure of the OT-OTR-Mg 2+ coordination complex as identified using cryo-electron (Meyerowitz et al, 2022). Thus, alterations of serum or exogenously applied Mg 2+ levels should play a critical role in OTR activity and consequently the physiological and psychological functions listed above.…”

Section: Introductionmentioning

confidence: 99%

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Impact of magnesium on oxytocin receptor function

Bharadwaj

Meyerowitz

Zou

et al. 2022

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Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to activation of OTR, and low serum Mg2+ concentration is predictive of migraine headache. We, therefore, examined the functional impact of Mg2+ concentration on OT-OTR binding efficacy using three complimentary bioassays. Experimental Approach: Bioluminescence resonance energy transfer assay was used to investigate the impact of Mg2+ on G-protein activation secondary to OT-OTR binding. Current clamp recordings of rat trigeminal ganglia neurons (TG) measured the impact of Mg2+ on OT-induced reduction in excitability. Finally, we assessed the impact of Mg2+ on intranasal OT-induced craniofacial analgesia in rats. Key Results: Mg2+ is an essential cofactor for full OT-OTR agonism and concentration-dependently increased Gq and G11 activation in OTR-transfected HEK cells, although OT-OTR binding did not reach maximal efficacy at physiologic concentrations. OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability; the addition of 1.75mM Mg2+ significantly enhanced this effect. Finally, while intranasal application of OT produced dose-dependent craniofacial analgesia; Mg2+ significantly enhanced these effects. Conclusion and Implications: Mg2+ concentration is critical to OT-OTR signaling, and OT efficacy may be limited by low ambient Mg2+ levels. The addition of Mg2+ to OT formulations may improve its efficacy in reducing headache pain as well as for other oxytocin-dependent processes.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of magnesium on oxytocin receptor function

Bharadwaj

Meyerowitz

Zou

et al. 2022

Preprint

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“…The last of these, OTR affinity, is closely modulated by the local concentration of the magnesium cation (Mg 2+ ) which acts as an essential cofactor, dramatically increasing the affinity of OTR for OT [ 8 , 12 , 13 ]. Recently, Meyerowitz et al [ 14 ] published the structure of the OT-OTR-Mg 2+ coordination complex as identified using cryo-electron microscopy, demonstrating the critical role that Mg 2+ plays in OT binding to OTR. Thus, alterations of serum or exogenously applied Mg 2+ levels should play a critical role in OTR activity and consequently the physiological and psychological functions listed above.…”

Section: Introductionmentioning

confidence: 99%

Impact of Magnesium on Oxytocin Receptor Function

et al. 2022

View full text Add to dashboard Cite

Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to the activation of the OTR, and a low serum Mg2+ concentration is predictive of a migraine headache. We, therefore, examined the functional impact of Mg2+ concentration on OT-OTR binding efficacy using two complimentary bioassays. Experimental Approach: Current clamp recordings of rat trigeminal ganglia (TG) neurons measured the impact of Mg2+ on an OT-induced reduction in excitability. In addition, we assessed the impact of Mg2+ on intranasal OT-induced craniofacial analgesia in rats. Key Results: While OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, the addition of 1.75 mM Mg2+ significantly enhanced this effect. Similarly, while the intranasal application of OT produced dose-dependent craniofacial analgesia, Mg2+ significantly enhanced these effects. Conclusions and Implications: OT efficacy may be limited by low ambient Mg2+ levels. The addition of Mg2+ to OT formulations may improve its efficacy in reducing headache pain as well as for other OT-dependent processes.

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