Targeting ryanodine receptors to treat human diseases

Marks, Andrew R.

doi:10.1172/jci162891

Cited by 32 publications

(32 citation statements)

References 88 publications

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“…The facts that we observed no changes in neuronal AT1aRs, that we failed to detect AT1aRs in astrocytes, and that Ang II-mediated neuronal dysfunction has not yet been reported in the absence of glial cell activation, 74 would argue against a neuronal/ astrocyte critical contribution. On the contrary, it is worth acknowledging that Ang II can suppress LTP in hippocampal neurons 75 and that other mechanisms, including leaky ryanodine receptors, 76 could also contribute to cognitive impairment in this HF rat model.…”

Section: Ang Ii-at1r Signaling Contributes To Hippocampal Neuroinflam...mentioning

confidence: 86%

Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats

et al. 2023

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Background: Heart failure (HF) is a debilitating disease affecting >64 million people worldwide. In addition to impaired cardiovascular performance and associated systemic complications, most patients with HF suffer from depression and substantial cognitive decline. Although neuroinflammation and brain hypoperfusion occur in humans and rodents with HF, the underlying neuronal substrates, mechanisms, and their relative contribution to cognitive deficits in HF remains unknown. Methods: To address this critical gap in our knowledge, we used a well-established HF rat model that mimics clinical outcomes observed in the human population, along with a multidisciplinary approach combining behavioral, electrophysiological, neuroanatomical, molecular and systemic physiological approaches. Results: Our studies support neuroinflammation, hypoperfusion/hypoxia, and neuronal deficits in the hippocampus of HF rats, which correlated with the progression and severity of the disease. An increased expression of AT1aRs (Ang [angiotensin] II receptor type 1a) in hippocampal microglia preceded the onset of neuroinflammation. Importantly, blockade of AT1Rs with a clinically used therapeutic drug (Losartan), and delivered in a clinically relevant manner, efficiently reversed neuroinflammatory end points (but not hypoxia ones), resulting in turn in improved cognitive performance in HF rats. Finally, we show than circulating Ang II can leak and access the hippocampal parenchyma in HF rats, constituting a possible source of Ang II initiating the neuroinflammatory signaling cascade in HF. Conclusions: In this study, we identified a neuronal substrate (hippocampus), a mechanism (Ang II–driven neuroinflammation) and a potential neuroprotective therapeutic target (AT1aRs) for the treatment of cognitive deficits in HF.

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Section: Ang Ii-at1r Signaling Contributes To Hippocampal Neuroinflam...mentioning

confidence: 86%

Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats

et al. 2023

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Section: Therapeutic Concepts and Future Directions: Targeting The We...mentioning

confidence: 99%

“…Although still in the preliminary stages, work has been done developing therapeutics for previously mentioned leaky RyR channels, both in the cardiomyopic and muscular domains as well as from the perspective of neurodegeneration. 104 Many advances in developing RyR-based therapeutics are dependent on a wholistic approach spanning genomic studies and structural imaging, both of which have seen rapid development since the inception of the calcium hypothesis. Interventions aimed at directly lowering abnormally increased [Ca 2+ ] c to normal levels are expected to produce broader therapeutic outcomes, as this Ca 2+ elevation is at the core of synaptic dysfunction, inciting pathophysiological cascades and inducing neuronal apoptosis.…”

Section: Therapeutic Concepts and Future Directions: Targeting The We...mentioning

confidence: 99%

Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

Webber

Fivaz²,

Stutzmann

et al. 2023

Alzheimer's & Dementia

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This review discusses the driving principles that may underlie neurodegeneration in dementia, represented most dominantly by Alzheimer's disease (AD). While a myriad of different disease risk factors contribute to AD, these ultimately converge to a common disease outcome. Based on decades of research, a picture emerges where upstream risk factors combine in a feedforward pathophysiological cycle, culminating in a rise of cytosolic calcium concentration ([Ca2+]c) that triggers neurodegeneration. In this framework, positive AD risk factors entail conditions, characteristics, or lifestyles that initiate or accelerate self‐reinforcing cycles of pathophysiology, whereas negative risk factors or therapeutic interventions, particularly those mitigating elevated [Ca2+]c, oppose these effects and therefore have neuroprotective potential.

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“…RyR2 is expressed in the heart and multiple brain regions [9,78]. Recent work associates pathological changes at the S2808 site of RyR2 function with excessive phosphorylation and cognitive deficits [15,79,80].…”

Section: Discussionmentioning

confidence: 99%

The Role of Ryanodine Receptor 2 in Drug-Associated Learning

Barber,

Vizcarra,

Zilch

et al. 2023

Preprint

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Type-2 ryanodine receptor (RyR2) ion channels facilitate the release of Ca2+from stores and serve an important function in neuroplasticity. The role for RyR2 in hippocampal-dependent learning and memory is well established and chronic hyperphosphorylation of RyR2 (RyR2P) is associated with pathological calcium leakage and cognitive disorders, including Alzheimer’s disease. By comparison, little is known about the role of RyR2 in the ventral medial prefrontal cortex (vmPFC) circuitry important for working memory, decision making, and reward seeking. Here, we evaluated the basal expression and localization of RyR2 and RyR2P in the vmPFC. Next, we employed an operant model of sucrose, cocaine, or morphine self-administration (SA) followed by a (reward-free) recall test, to reengage vmPFC neurons and reactivate reward-seeking and re-evaluated the expression and localization of RyR2 and RyR2P in vmPFC. Under basal conditions, RyR2 was expressed in pyramidal cells but not regularly detected in PV/SST interneurons. On the contrary, RyR2P was rarely observed in PFC somata and was restricted to a different subcompartment of the same neuron - the apical dendrites of layer-5 pyramidal cells. Chronic SA of drug (cocaine or morphine) and nondrug (sucrose) rewards produced comparable increases in RyR2 protein expression. However, recalling either drug reward impaired the usual localization of RyR2P in dendrites and markedly increased its expression in somata immunoreactive for Fos, a marker of highly activated neurons. These effects could not be explained by chronic stress or drug withdrawal and instead appeared to require a recall experience associated with prior drug SA. In addition to showing the differential distribution of RyR2/RyR2P and affirming the general role of vmPFC in reward learning, this study provides information on the propensity of addictive drugs to redistribute RyR2P ion channels in a neuronal population engaged in drug-seeking. Hence, focusing on the early impact of addictive drugs on RyR2 function may serve as a promising approach to finding a treatment for substance use disorders.

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Targeting ryanodine receptors to treat human diseases

Abstract: Conflict of interest: ARM is the founding scientist for ARMGO Pharma Inc., a biotechnology company focused on developing RyR-targeted therapeutics, and both he and Columbia University have stock in the company.

Cited by 32 publications

References 88 publications

Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats

Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats

Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

The Role of Ryanodine Receptor 2 in Drug-Associated Learning

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