scholarly journals Designer small molecules to target calcium signalling

2015 ◽  
Vol 43 (3) ◽  
pp. 417-425 ◽  
Author(s):  
Joanna M. Swarbrick ◽  
Andrew M. Riley ◽  
Stephen J. Mills ◽  
Barry V.L. Potter
Keyword(s):  
Nicotinic Acid ◽  
Small Molecules ◽  
Conformational Changes ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Synthetic Analogues ◽  
Binding Model ◽  
Transient Receptor Potential Melastatin ◽  
Inositol 1,4,5 Trisphosphate

Synthetic compounds open up new avenues to interrogate and manipulate intracellular Ca2+ signalling pathways. They may ultimately lead to drug-like analogues to intervene in disease. Recent advances in chemical biology tools available to probe Ca2+ signalling are described, with a particular focus on those synthetic analogues from our group that have enhanced biological understanding or represent a step towards more drug-like molecules. Adenophostin (AdA) is the most potent known agonist at the inositol 1,4,5-trisphosphate receptor (IP3R) and synthetic analogues provide a binding model for receptor activation and channel opening. 2-O-Modified inositol 1,4,5-trisphosphate (IP3) derivatives that are partial agonists at the IP3R reveal key conformational changes of the receptor upon ligand binding. Biphenyl polyphosphates illustrate that simple non-inositol surrogates can be engineered to give prototype IP3R agonists or antagonists and act as templates for protein co-crystallization. Cyclic adenosine 5′-diphosphoribose (cADPR) can be selectively modified using total synthesis, generating chemically and biologically stable tools to investigate Ca2+ release via the ryanodine receptor (RyR) and to interfere with cADPR synthesis and degradation. The first neutral analogues with a synthetic pyrophosphate bioisostere surprisingly retain the ability to release Ca2+, suggesting a new route to membrane-permeant tools. Adenosine 5′-diphosphoribose (ADPR) activates the Ca2+-, Na+- and K+-permeable transient receptor potential melastatin 2 (TRPM2) cation channel. Synthetic ADPR analogues provide the first structure-activity relationship (SAR) for this emerging messenger and the first functional antagonists. An analogue based on the nicotinic acid motif of nicotinic acid adenine dinucleotide phosphate (NAADP) antagonizes NAADP-mediated Ca2+ release in vitro and is effective in vivo against induced heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of targeted small molecules.

scholarly journals Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 231 ◽  
Author(s):  
Dae Hong ◽  
Bo Choi ◽  
A Kho ◽  
Song Lee ◽  
Jeong Jeong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Zinc Translocation

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

scholarly journals The Transient Receptor Potential Melastatin 7 (TRPM7) Inhibitors Suppress Seizure-Induced Neuron Death by Inhibiting Zinc Neurotoxicity

2020 ◽  
Vol 21 (21) ◽  
pp. 7897
Author(s):  
Jeong Hyun Jeong ◽  
Song Hee Lee ◽  
A Ra Kho ◽  
Dae Ki Hong ◽  
Dong Hyeon Kang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Divalent Cations ◽  
Neurological Diseases ◽  
Receptor Potential ◽  
Neuron Death ◽  
Intracellular Zinc ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Induced Neuron

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood–brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death.

scholarly journals Structural basis for pharmacological modulation of the TRPC6 channel

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yonghong Bai ◽  
Xinchao Yu ◽  
Hao Chen ◽  
Daniel Horne ◽  
Ryan White ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Bound States ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Structural Basis ◽  
Future Design ◽  
Subunit Interface ◽  
Transient Receptor ◽  
Small Molecule Modulators

Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.

scholarly journals Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Tiantian Zhu ◽  
Moli Zhu ◽  
Yue Qiu ◽  
Zeqing Wu ◽  
Ning Huang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Vascular Dementia ◽  
Vascular Injury ◽  
Cognitive Deficits ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Neuronal Cell ◽  
Structural Plasticity ◽  
Neuroprotective Activity ◽  
Transient Receptor Potential Melastatin

Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur’s effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.

scholarly journals A Role for H2O2 and TRPM2 in the Induction of Cell Death: Studies in KGN Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 518 ◽  
Author(s):  
Carsten Theo Hack ◽  
Theresa Buck ◽  
Konstantin Bagnjuk ◽  
Katja Eubler ◽  
Lars Kunz ◽  
...  
Keyword(s):  
Cell Death ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Receptor Potential ◽  
Granulosa Cell Tumor ◽  
Nadph Oxidase 4 ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel

Recent studies showed that KGN cells, derived from a human granulosa cell tumor (GCT), express NADPH oxidase 4 (NOX4), an important source of H2O2. Transient receptor potential melastatin 2 (TRPM2) channel is a Ca2+ permeable cation channel that can be activated by H2O2 and plays an important role in cellular functions. It is also able to promote susceptibility to cell death. We studied expression and functionality of TRPM2 in KGN cells and examined GCT tissue microarrays (TMAs) to explore in vivo relevance. We employed live cell, calcium and mitochondrial imaging, viability assays, fluorescence activated cell sorting (FACS) analysis, Western blotting and immunohistochemistry. We confirmed that KGN cells produce H2O2 and found that they express functional TRPM2. H2O2 increased intracellular Ca2+ levels and N-(p-Amylcinnamoyl)anthranilic acid (ACA), a TRPM2 inhibitor, blocked this action. H2O2 caused mitochondrial fragmentation and apoptotic cell death, which could be attenuated by a scavenger (Trolox). Immunohistochemistry showed parallel expression of NOX4 and TRPM2 in all 73 tumor samples examined. The results suggest that GCTs can be endowed with a system that may convey susceptibility to cell death. If so, induction of oxidative stress may be beneficial in GCT therapy. Our results also imply a therapeutic potential for TRPM2 as a drug target in GCTs.

scholarly journals Structural insights into TRPM8 inhibition and desensitization

Science ◽  
2019 ◽  
Vol 365 (6460) ◽  
pp. 1434-1440 ◽  
Author(s):  
Melinda M. Diver ◽  
Yifan Cheng ◽  
David Julius
Keyword(s):  
Conformational Changes ◽  
Calcium Binding ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Chemical Structures ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Large Rearrangements

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo–electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

scholarly journals CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5413
Author(s):  
Luciana M. Leo ◽  
Mary E. Abood
Keyword(s):  
Adverse Effects ◽  
G Protein ◽  
Conformational Changes ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.

scholarly journals TRPM7 Ion Channel: Oncogenic Roles and Therapeutic Potential in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6322
Author(s):  
Clément Cordier ◽  
Natalia Prevarskaya ◽  
V’yacheslav Lehen’kyi
Keyword(s):  
Breast Cancer ◽  
Ion Channel ◽  
Therapeutic Target ◽  
Transient Receptor Potential ◽  
Kinase Activity ◽  
Therapeutic Potential ◽  
Migration And Invasion ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition ◽  
Transient Receptor Potential Melastatin

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a divalent cations permeant channel but also has intrinsic serine/threonine kinase activity. It is ubiquitously expressed in normal tissues and studies have indicated that it participates in important physiological and pharmacological processes through its channel-kinase activity, such as calcium/magnesium homeostasis, phosphorylation of proteins involved in embryogenesis or the cellular process. Accumulating evidence has shown that TRPM7 is overexpressed in human pathologies including breast cancer. Breast cancer is the second leading cause of cancer death in women with an incidence rate increase of around 0.5% per year since 2004. The overexpression of TRPM7 may be associated with a poor prognosis in breast cancer patients, so more efforts are needed to research a new therapeutic target. TRPM7 regulates the levels of Ca2+, which can alter the signaling pathways involved in survival, cell cycle progression, proliferation, growth, migration, invasion, epithelial-mesenchymal transition and thus determines cell behavior, promoting tumor development. This work provides a complete overview of the TRPM7 ion channel and its main involvements in breast cancer. Special consideration is given to the modulation of the channel as a potential target in breast cancer treatment by inhibition of proliferation, migration and invasion. Taken together, these data suggest the potential exploitation of TRPM7 channel-kinase as a therapeutic target and a diagnostic biomarker.

scholarly journals NAADP induces pH changes in the lumen of acidic Ca2+ stores

2007 ◽  
Vol 402 (2) ◽  
pp. 301-310 ◽  
Author(s):  
Anthony J. Morgan ◽  
Antony Galione
Keyword(s):  
Nicotinic Acid ◽  
Direct Effect ◽  
Sea Urchin ◽  
Cell Types ◽  
Receptor Activation ◽  
Fluorescence Measurements ◽  
Low Concentrations ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Organelles ◽  
First Time

NAADP (nicotinic acid–adenine dinucleotide phosphate)-induced Ca2+ release has been proposed to occur selectively from acidic stores in several cell types, including sea urchin eggs. Using fluorescence measurements, we have investigated whether NAADP-induced Ca2+ release alters the pHL (luminal pH) within these acidic stores in egg homogenates and observed their prompt, concentration-dependent alkalinization by NAADP (but not β-NAD+ or NADP). Like Ca2+ release, the pHL change was desensitized by low concentrations of NAADP suggesting it was secondary to NAADP receptor activation. Moreover, this was a direct effect of NAADP upon the acidic stores and not secondary to increases in cytosolic Ca2+ as it was not mimicked by IP3 (inositol 1,4,5-trisphosphate), cADPR (cyclic adenine diphosphoribose), ionomycin, thapsigargin or by direct addition of Ca2+, and was not blocked by EGTA. The results of the present study further support acidic stores as targets for NAADP and for the first time reveal an adjunct role for NAADP in regulating the pHL of intracellular organelles.

Paraquat-induced intracellular Zn2+ dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum

2021 ◽  
Author(s):  
Haruna Tamura ◽  
Ryusuke Nishio ◽  
Nana Saeki ◽  
Misa Katahira ◽  
Hiroki Morioka ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Ampa Receptors ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Substantia Nigra Pars Compacta ◽  
Extracellular Glutamate ◽  
Transient Receptor Potential Melastatin ◽  
The Difference ◽  
Dopaminergic Degeneration

Abstract Parkinson's disease (PD) is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.

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