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Resveratrol Directly Controls the Activity of Neuronal Ryanodine Receptors at the Single-Channel Level

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Abstract

Calcium ion dyshomeostasis contributes to the progression of many neurodegenerative diseases and represents a target for the development of neuroprotective therapies, as reported by Duncan et al. (Molecules 15(3):1168–95, 2010), LaFerla (Nat Rev Neurosci 3(11):862–72, 2002), and Niittykoshi et al. (Invest Ophthalmol Vis Sci 51(12):6387–93, 2010). Dysfunctional ryanodine receptors contribute to calcium ion dyshomeostasis and potentially to the pathogenesis of neurodegenerative diseases by generating abnormal calcium ion release from the endoplasmic reticulum, according to Bruno et al. (Neurobiol Aging 33(5):1001 e1–6, 2012) and Stutzmann et al. (J Neurosci 24(2):508–13, 2004). Since ryanodine receptors share functional and structural similarities with potassium channels, as reported by Lanner et al. (Cold Spring Harb Perspect Biol 2(11):a003996, 2010), and small molecules with anti-oxidant properties, such as resveratrol (3,5,4′-trihydroxy-trans-stilbene), directly control the activity of potassium channels, according to Wang et al. (J Biomed Sci 23(1):47, 2016), McCalley et al. (Molecules 19(6):7327–40, 2014), Novakovic et al. (Mol Hum Reprod 21(6):545–51, 2015), Li et al. (Cardiovasc Res 45(4):1035–45, 2000), Gopalakrishnan et al. (Br J Pharmacol 129(7):1323–32, 2000), and Hambrock et al. (J Biol Chem 282(5):3347–56, 2007), we hypothesized that trans-resveratrol can modulate intracellular calcium signaling through direct binding and functional regulation of ryanodine receptors. The goal of our study was to identify and measure the control of ryanodine receptor activity by trans-resveratrol. Mechanisms of calcium signaling mediated by the direct interaction between trans-resveratrol and ryanodine receptors were identified and measured with single-channel electrophysiology. Addition of trans-resveratrol to the cytoplasmic face of the ryanodine receptor increased single-channel activity at physiological and elevated pathophysiological cytoplasmic calcium ion concentrations. The open probability of the channel increases after interacting with the small molecule in a dose-dependent manner, but remains also dependent on the concentration of its physiological ligand, cytoplasmic-free calcium ions. This study provides the first evidence of a direct functional interaction between trans-resveratrol and ryanodine receptors. Such functional control of ryanodine receptors by trans-resveratrol as a novel mechanism of action could provide additional rationales for the development of novel therapeutic strategies to treat and prevent neurodegenerative diseases.

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Funding

Research reported in this publication was supported in part by grants from the National Eye Institute (EY014227 and EY022774), the Institute on Aging (AG027956), and the National Center for Research Resources and National Institute of General Medical Sciences (RR027093) of the National Institutes of Health (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research and a Challenge Grant from Research to Prevent Blindness (PK) is gratefully recognized.

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  1. Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA

    Jacob G. Kraus & Peter Koulen

  2. Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA

    Peter Koulen

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Kraus, J.G., Koulen, P. Resveratrol Directly Controls the Activity of Neuronal Ryanodine Receptors at the Single-Channel Level. Mol Neurobiol 57, 422–434 (2020). https://doi.org/10.1007/s12035-019-01705-7

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