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Article: Mutational Analysis of Sigma-1 Receptor's Role in Synaptic Stability.

Ryskamp, Daniel A / Zhemkov, Vladimir / Bezprozvanny, Ilya

2019 Volume 13, Page(s) 1012

Abstract: Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) resident transmembrane protein. In our previous experiments, we demonstrated neuroprotective effects of pridopidine, an agonist of S1R, in cellular and animal models of Huntington's disease (HD) and ...

Abstract	Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) resident transmembrane protein. In our previous experiments, we demonstrated neuroprotective effects of pridopidine, an agonist of S1R, in cellular and animal models of Huntington's disease (HD) and Alzheimer's disease (AD). Consistent with previous observations, deletion of endogenous S1R with CRISPR/Cas9 in cultured hippocampal neurons resulted in fewer mushroom-shaped dendritic spines. Overexpression of human S1R restored mushroom spine density to control levels. In contrast, overexpression of S1R with the Δ31-50 deletion (linked to distal hereditary motor neuropathy) or the E102Q mutation (linked to amyotrophic lateral sclerosis) destabilized mushroom spines. Recently a crystal structure of S1R was determined in lipidic cubic phase. In the present study, we took an advantage of this structural information and performed docking studies with pridopidine and the S1R structural model. We generated a series of S1R point mutations based on residues predicted to be involved in direct association with pridopidine. We discovered that all ligand binding-site mutants were able to compensate for loss of endogenous S1R. However, most of these mutants were not able to support pridopidine-induced rescue of mushroom spines in presenilin-1-mutant cultures. Our mutational analysis was in agreement with
Language	English
Publishing date	2019-09-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.01012
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Article: Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases.

Ryskamp, Daniel A / Korban, Svetlana / Zhemkov, Vladimir / Kraskovskaya, Nina / Bezprozvanny, Ilya

Frontiers in neuroscience

2019 Volume 13, Page(s) 862

Abstract: Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral ... ...

Abstract	Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer's (AD) and Huntington's diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.
Language	English
Publishing date	2019-08-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.00862
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Article: UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.

Rijsketic, Daniel Ryskamp / Casey, Austen B / Barbosa, Daniel A N / Zhang, Xue / Hietamies, Tuuli M / Ramirez-Ovalle, Grecia / Pomrenze, Matthew / Halpern, Casey H / Williams, Leanne M / Malenka, Robert C / Heifets, Boris D

bioRxiv : the preprint server for biology

2023

Abstract: The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their ...

Abstract	The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.19.528997
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Article ; Online: UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.

Rijsketic, Daniel Ryskamp / Casey, Austen B / Barbosa, Daniel A N / Zhang, Xue / Hietamies, Tuuli M / Ramirez-Ovalle, Grecia / Pomrenze, Matthew B / Halpern, Casey H / Williams, Leanne M / Malenka, Robert C / Heifets, Boris D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2023 Volume 48, Issue 12, Page(s) 1798–1807

Abstract	The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos
MeSH term(s)	Mice ; Humans ; Animals ; Psilocybin/pharmacology ; Genes, Immediate-Early ; Brain/metabolism ; Hallucinogens/pharmacology ; Proto-Oncogene Proteins c-fos/metabolism
Chemical Substances	Psilocybin (2RV7212BP0) ; Hallucinogens ; Proto-Oncogene Proteins c-fos
Language	English
Publishing date	2023-05-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-023-01613-4
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Zs.A 2379: Show issues

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Article ; Online: TRPV4 links inflammatory signaling and neuroglial swelling.

Ryskamp, Daniel A / Iuso, Anthony / Križaj, David

Channels (Austin, Tex.)

2015 Volume 9, Issue 2, Page(s) 70–72

MeSH term(s)	Humans ; Inflammation/metabolism ; Inflammation/pathology ; Neuroglia/metabolism ; Neuroglia/pathology ; Signal Transduction ; TRPV Cation Channels/agonists ; TRPV Cation Channels/metabolism
Chemical Substances	TRPV Cation Channels ; TRPV4 protein, human
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article
ISSN	1933-6969
ISSN (online)	1933-6969
DOI	10.1080/19336950.2015.1017998
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Article ; Online: Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease.

Wu, Jun / Ryskamp, Daniel / Birnbaumer, Lutz / Bezprozvanny, Ilya

Journal of Huntington's disease

2018 Volume 7, Issue 1, Page(s) 35–50

Abstract: Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor ( ... ...

Abstract	Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) to InsP3. This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice. Objective: We sought to identify calcium channels supporting supranormal nSOC in HD MSNs and to validate these channels as potential therapeutic targets for HD. Methods: Cortico-striatal cultures were established from wild type and YAC128 HD mice and the density of MSN spines was quantified. The expression of candidate nSOC components was suppressed by RNAi knockdown and by CRISPR/Cas9 knockout. TRPC1 knockout mice were crossed with YAC128 HD mice for evaluation of motor performance in a beamwalk assay. Results: RNAi-mediated knockdown of TRPC1, TRPC6, Orai1, or Orai2, but not other TRPC isoforms or Orai3, rescued the density of YAC128 MSN spines. Knockdown of stromal interaction molecule 1 (STIM1), an ER calcium sensor and nSOC activator, also rescued YAC128 MSN spines. Knockdown of the same targets suppressed supranormal nSOC in YAC128 MSN spines. These channel subunits co-immunoprecipitated with STIM1 and STIM2 in synaptosomal lysates from mouse striata. Crossing YAC128 mice with TRPC1 knockout mice improved motor performance and rescued MSN spines in vitro and in vivo, indicating that inhibition of TRPC1 may serve as a neuroprotective strategy for HD treatment. Conclusions: TRPC1 channels constitute a potential therapeutic target for treatment of HD.
MeSH term(s)	Animals ; Calcium/metabolism ; Corpus Striatum/metabolism ; Disease Models, Animal ; Huntington Disease/genetics ; Mice ; Mice, Knockout ; Motor Activity/genetics ; Neurons/metabolism ; TRPC Cation Channels/metabolism
Chemical Substances	TRPC Cation Channels ; transient receptor potential cation channel, subfamily C, member 1 ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-02-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ISSN	1879-6400
ISSN (online)	1879-6400
DOI	10.3233/JHD-170266
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Article: TRPV4: Cell type-specific activation, regulation and function in the vertebrate eye.

Lapajne, Luka / Rudzitis, Christopher N / Cullimore, Brenan / Ryskamp, Daniel / Lakk, Monika / Redmon, Sarah N / Yarishkin, Oleg / Krizaj, David

Current topics in membranes

2022 Volume 89, Page(s) 189–219

Abstract: The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and ... ...

Abstract	The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and sclera have specialized functions in ocular protection, transparency, accommodation, fluid regulation, metabolism and inflammatory signaling, which are required to enable function of the retina-light sensitive tissue in the posterior eye that transmits visual signals to relay centers in the midbrain. This process can be profoundly impacted by non-visual stimuli such as mechanical (tension, compression, shear), thermal, nociceptive, immune and chemical stimuli, which target these eye regions to induce pain and precipitate vision loss in glaucoma, diabetic retinopathy, retinal dystrophies, retinal detachment, cataract, corneal dysfunction, ocular trauma and dry eye disease. TRPV4, a polymodal nonselective cation channel, integrate non-visual inputs with homeostatic and signaling functions of the eye. The TRPV4 gene is expressed in most if not all ocular tissues, which vary widely with respect to the mechanisms of TRPV4 channel activation, modulation, oligomerization, and participation in protein- and lipid interactions. Under- and overactivation of TRPV4 may affect intraocular pressure, maintenance of blood-retina barriers, lens accommodation, neuronal function and neuroinflammation. Because TRPV4 dysregulation precipitates many pathologies across the anterior and posterior eye, the channel could be targeted to mitigate vision loss.
MeSH term(s)	Animals ; Cornea/metabolism ; Lipids ; Retina ; TRPV Cation Channels/metabolism ; Vertebrates/metabolism
Chemical Substances	Lipids ; TRPV Cation Channels
Language	English
Publishing date	2022-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1063-5823
ISSN	1063-5823
DOI	10.1016/bs.ctm.2022.07.005
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Article: TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision.

Ryskamp, Daniel A / Redmon, Sarah / Jo, Andrew O / Križaj, David

Cells

2014 Volume 3, Issue 3, Page(s) 914–938

Abstract: Transient Receptor Potential Vanilloid 1 (TRPV1) subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in ... ...

Abstract	Transient Receptor Potential Vanilloid 1 (TRPV1) subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC) axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.
Language	English
Publishing date	2014-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661518-6
ISSN	2073-4409
ISSN	2073-4409
DOI	10.3390/cells3030914
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Article: Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice.

Pomrenze, Matthew B / Vaillancourt, Sam / Llorach, Pierre / Rijsketic, Daniel Ryskamp / Casey, Austen B / Gregory, Nicholas / Salgado, Juliana S / Malenka, Robert C / Heifets, Boris D

bioRxiv : the preprint server for biology

2024

Abstract: Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone ...

Abstract	Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both μOR (MOR) and PKCμ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.03.583196
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Article ; Online: Metformin inhibits RAN translation through PKR pathway and mitigates disease in

Zu, Tao / Guo, Shu / Bardhi, Olgert / Ryskamp, Daniel A / Li, Jian / Khoramian Tusi, Solaleh / Engelbrecht, Avery / Klippel, Kelena / Chakrabarty, Paramita / Nguyen, Lien / Golde, Todd E / Sonenberg, Nahum / Ranum, Laura P W

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 31, Page(s) 18591–18599

Abstract: Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). ... ...

Abstract	Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G
MeSH term(s)	Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Brain/metabolism ; Brain/pathology ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism ; Disease Models, Animal ; Frontotemporal Dementia/metabolism ; Humans ; Metformin/pharmacology ; Mice ; Mice, Transgenic ; Microsatellite Repeats/genetics ; Protein Biosynthesis/drug effects ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	C9orf72 Protein ; Metformin (9100L32L2N) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2020-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2005748117
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