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Mammalian Melatonin Agonist Pharmaceuticals Stimulate Rhomboid Proteins in Plants.

ABSTRACT: Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis Arabidopsis seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. Ramelteon was found both to mimic and competitively inhibit melatonin metabolism in plants. Due to the higher selectivity of ramelteon for the MT1 receptor type in humans, a sequence homology search for MT1 in Arabidopsis identified the rhomboid-like protein 7 (RBL7). In physiological studies, Arabidopsis rbl7 mutants were less responsive to ramelteon and melatonin. Quantum dot visualizations of the effects of ramelteon on melatonin binding to root cell membranes revealed a potential mechanism. We propose that RBL7 is a melatonin-interacting protein that directs root architecture and growth in a mechanism that is responsive to environmental factors.

SUBMITTER: Erland LAE

PROVIDER: S-EPMC9313243 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Mammalian Melatonin Agonist Pharmaceuticals Stimulate Rhomboid Proteins in Plants.

Erland Lauren A E LAE Dumigan Christopher R CR Forsyth Jillian A JA Frolova Liubov L Yasunaga Adam B AB Pun Winnie W Li Isaac T S ITS Deyholos Michael K MK Murch Susan J SJ

Biomolecules 20220624 7

Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis <i>Arabidopsis</i> seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. ...[more]

PMID: 35883439

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Project description:Integrated in silico chemical clustering and melatonin receptor molecular modeling combined with in vitro 2-[125I]-iodomelatonin competition binding were used to identify carbamate insecticides with affinity for human melatonin receptor 1 (hMT1) and human melatonin receptor 2 (hMT2). Saturation and kinetic binding studies with 2-[125I]-iodomelatonin revealed lead carbamates (carbaryl, fenobucarb, bendiocarb, carbofuran) to be orthosteric ligands with antagonist apparent efficacy at hMT1 and agonist apparent efficacy at hMT2 Furthermore, using quantitative receptor autoradiography in coronal brain slices from C3H/HeN mice, carbaryl, fenobucarb, and bendiocarb competed for 2-[125I]-iodomelatonin binding in the suprachiasmatic nucleus (SCN), paraventricular nucleus of the thalamus (PVT), and pars tuberalis (PT) with affinities similar to those determined for the hMT1 receptor. Carbaryl (10 mg/kg i.p.) administered in vivo also competed ex vivo for 2-[125I]-iodomelatonin binding to the SCN, PVT, and PT, demonstrating the ability to reach brain melatonin receptors in C3H/HeN mice. Furthermore, the same dose of carbaryl given to C3H/HeN mice in constant dark for three consecutive days at subjective dusk (circadian time 10) phase-advanced circadian activity rhythms (mean = 0.91 hours) similar to melatonin (mean = 1.12 hours) when compared with vehicle (mean = 0.04 hours). Carbaryl-mediated phase shift of overt circadian activity rhythm onset is likely mediated via interactions with SCN melatonin receptors. Based on the pharmacological actions of carbaryl and other carbamate insecticides at melatonin receptors, exposure may modulate time-of-day information conveyed to the master biologic clock relevant to adverse health outcomes. SIGNIFICANCE STATEMENT: In silico chemical clustering and molecular modeling in conjunction with in vitro bioassays identified several carbamate insecticides (i.e., carbaryl, carbofuran, fenobucarb, bendiocarb) as pharmacologically active orthosteric melatonin receptor 1 and 2 ligands. This work further demonstrated that carbaryl competes for melatonin receptor binding in the master biological clock (suprachiasmatic nucleus) and phase-advances overt circadian activity rhythms in C3H/HeN mice, supporting the relevance of circadian effects when interpreting toxicological findings related to carbamate insecticide exposure.

Dataset Information

Mammalian Melatonin Agonist Pharmaceuticals Stimulate Rhomboid Proteins in Plants.

Publications

Mammalian Melatonin Agonist Pharmaceuticals Stimulate Rhomboid Proteins in Plants.

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