Ophthalmate is a new regulator of motor functions via CaSR: Implications for movement disorders

Sammy Alhassen; Derk Hogenkamp; Hung Anh Nguyen; Saeed Al Masri; Geoffrey W Abbott; Olivier Civelli; Amal Alachkar

doi:10.1093/brain/awae097

Ophthalmate is a new regulator of motor functions via CaSR: Implications for movement disorders

Brain. 2024 Mar 27:awae097. doi: 10.1093/brain/awae097. Online ahead of print.

Authors

Sammy Alhassen¹, Derk Hogenkamp^{1

2}, Hung Anh Nguyen¹, Saeed Al Masri¹, Geoffrey W Abbott², Olivier Civelli^{1

3}, Amal Alachkar^{1

4

5}

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, CA 92697, USA.
² Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California Irvine, CA 92697, USA.
³ Department of Developmental and Cell Biology, University of California Irvine, CA 92697.
⁴ Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California Irvine, CA 92697, USA.
⁵ UC Irvine Center for the Neurobiology of Learning and Memory, University of California Irvine, CA 92697, USA.

PMID: 38537648
DOI: 10.1093/brain/awae097

Abstract

Dopamine's role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms. In mouse models of Parkinson's Disease (PD), we observed that L-DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC). Remarkably, the motor activity response to L-DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 hours, compared to when L-DOPA was administered alone. This suggests an alternative pathway or mechanism, independent of dopamine signaling, mediating the motor functions. We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis. Our results revealed that the peak in motor activity induced by NSD1015/L-DOPA in PD mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (OA, also known as ophthalmate in its anionic form). Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in PD mice in a dose-dependent manner. We investigated the molecular mechanisms underlying ophthalmate's action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR). Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR. The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders.

Keywords: CaSR; Parkinson’s disease; dopamine; motor; ophthalmate.

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