Elena Kaznacheyeva - Academia.edu (original) (raw)

Papers by Elena Kaznacheyeva

Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage... more Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage and diabetic nephropathy. Previous studies demonstrated that TRPC6 channels play a pivotal role in podocyte function and their dysregulation is associated with development of different kidney diseases including nephropathy. It was assumed that activation of TRPC6 channels leads directly to the Ca2+ influx into cells. Another Ca2+ influx pathway, a store-operated Ca2+ entry (SOCE) via ORAI channels, was also shown to be disturbed during the diabetes development. Here, using single channel patch clamp technique, we demonstrated that non-selective cationic TRPC6 channels are sensitive to the Ca2+ store depletion in human podocyte cell line Ab8/13 and in freshly isolated rat glomerular podocytes. Ca2+ imaging indicated the involvement of ORAI and sodium-calcium exchanger (NCX) in Ca2+ entry induced upon store depletion. Ca2+ inflow by NCX is a result of pronounced TRPC6-mediated Na+ influx ...

International Journal of Molecular Sciences

Quinazoline derivatives have various pharmacological activities and are widely used in clinical p... more Quinazoline derivatives have various pharmacological activities and are widely used in clinical practice. Here, we reviewed the proposed mechanisms of the physiological activity of the quinazoline derivative EVP4593 and perspectives for its clinical implication. We summarized the accumulated data about EVP4593 and focused on its activities in different models of Huntington’s disease (HD), including patient-specific iPSCs-based neurons. To make a deeper insight into its neuroprotective role in HD treatment, we discussed the ability of EVP4593 to modulate calcium signaling and reduce the level of the huntingtin protein. Moreover, we described possible protective effects of EVP4593 in other pathologies, such as oncology, cardiovascular diseases and parasite invasion. We hope that comprehensive analyses of the molecular mechanisms of EVP4593 activity will allow for the expansion of the scope of the EVP4593 application.

Neuroscience Bulletin, Oct 14, 2022

Molecular Neurobiology, 2021

Impairment of proteostasis network is one of the characteristic features of many age-related neur... more Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington's disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

International Journal of Molecular Sciences

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeo... more Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry med...

Biochemical and Biophysical Research Communications

International Journal of Molecular Sciences

Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in s... more Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in store-operated Ca2+ entry (SOCE). Ca2+ release through inositol 1,4,5-trisphosphate receptor (IP3R) and subsequent Ca2+ store depletion activate STIM (stromal interaction molecules) proteins, sensors of intraluminal Ca2+, which, in turn, open the Orai channels in plasma membrane. Downstream to this process could be activated TRPC (transient receptor potential-canonical) calcium permeable channels. Using single channel patch-clamp technique we found that a local Ca2+ entry through TRPC1 channels activated endogenous Ca2+-activated chloride channels (CaCCs) with properties similar to Anoctamin6 (TMEM16F). Our data suggest that their outward rectification is based on the dependence from membrane potential of both the channel conductance and the channel activity: (1) The conductance of active CaCCs highly depends on the transmembrane potential (from 3 pS at negative potentials till 60 pS at p...

International Journal of Molecular Sciences, 2021

The actin cytoskeleton of podocytes plays a central role in the functioning of the filtration bar... more The actin cytoskeleton of podocytes plays a central role in the functioning of the filtration barrier in the kidney. Calcium entry into podocytes via TRPC6 (Transient Receptor Potential Canonical 6) channels leads to actin cytoskeleton rearrangement, thereby affecting the filtration barrier. We hypothesized that there is feedback from the cytoskeleton that modulates the activity of TRPC6 channels. Experiments using scanning ion-conductance microscopy demonstrated a change in migration properties in podocyte cell cultures treated with cytochalasin D, a pharmacological agent that disrupts the actin cytoskeleton. Cell-attached patch-clamp experiments revealed that cytochalasin D increases the activity of TRPC6 channels in CHO (Chinese Hamster Ovary) cells overexpressing the channel and in podocytes from freshly isolated glomeruli. Furthermore, it was previously reported that mutation in ACTN4, which encodes α-actinin-4, causes focal segmental glomerulosclerosis and solidifies the actin...

Acta Naturae, 2010

ABSTARCT Store-operated channels are major calcium influx pathways in nonexitable cells. Homer sc... more ABSTARCT Store-operated channels are major calcium influx pathways in nonexitable cells. Homer scaffold proteins are well known for their role in regulating calcium signaling. Here we report on a detailed single-channel level characterization of native store-operated channels regulated by Homer scaffold proteins in A431 carcinoma cells. By applying the single-channel patch-clamp technique, we found that different types of store-operated calcium channels have different sensitivities to Homer proteins.

Acta Naturae, 2014

We have shown that the expression of full-length mutated huntingtin in human neuroblastoma cells ... more We have shown that the expression of full-length mutated huntingtin in human neuroblastoma cells (SK-N-SH) leads to an abnormal increase in calcium entry through store-operated channels. In this paper, the expression of the N-terminal fragment of mutated huntingtin (Htt138Q-1exon) is shown to be enough to provide an actual model for Huntingtons disease. We have shown that Htt138Q-1exon expression causes increased store-operated calcium entry, which is mediated by at least two types of channels in SK-N-SH cells with different reversal potentials. Calcium sensor, STIM1, is required for activation of store-operated calcium entry in these cells. The results provide grounds for considering the proteins responsible for the activation and maintenance of the store-operated calcium entry as promising targets for developing novel therapeutics for neurodegenerative diseases.

Acta Naturae, 2017

Huntingtons disease (HD) is a severe inherited neurodegenerative disorder characterized by motor ... more Huntingtons disease (HD) is a severe inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and mental impairment. At the molecular level, HD is caused by a mutation in the first exon of the gene encoding the huntingtin protein. The mutation results in an expanded polyglutamine tract at the N-terminus of the huntingtin protein, causing the neurodegenerative pathology. Calcium dyshomeostasis is believed to be one of the main causes of the disease, which underlies the great interest in the problem among experts in molecular physiology. Recent studies have focused on the development of animal and insect HD models, as well as patient-specific induced pluripotent stem cells (HD-iPSCs), to simulate the diseases progression. Despite a sesquicentennial history of HD studies, the issues of diagnosis and manifestation of the disease have remained topical. The present review addresses these issues.

Doklady Biological Sciences, 2008

Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections / translated from Russian, 2013

181 Activation of neurotransmitter receptors coupled to G proteins activating phospholipase C in ... more 181 Activation of neurotransmitter receptors coupled to G proteins activating phospholipase C in the plasma membrane (PM) of neuronal cells leads to an increase in the inositol 1,4,5 trisphosphate (IP3) con centration, the activation of inositol 1,4,5 trisphos phate receptor (IP3R), and, consequently, the release of calcium from the lumen of endoplasmic reticulum (ER). The increase in the calcium concentration in the cytoplasm activates ryanodine receptor (RyR), which also leads to release of calcium from ER [1]. Due to decrease in calcium concentration in ER, there are a signal transmission by calcium sensors STIM1 and STIM2 in ER to store operated calcium channels in PM, their activation, and calcium influx into the cell [2]. TRPC proteins (subunits of store operated calcium channels), metabotropic glutamate receptors (mGluR), RyR, and IP3R are the target pro teins specifically binding the adapter protein Homer 1c [3–6]. Oligomers of Homer 1c associated with target proteins form large molecular complexes and establish signal transmission in the area of postsynaptic density of neurons [4]. It has been suggested that adapter pro tein Homer 1c may take part in the regulation of sig naling from neurotransmitter to intracellular stores and store operated calcium channels in neurons.

Proceedings of the National Academy of Sciences, 2001

Activation of phospholipase C in nonexcitable cells causes the release of calcium (Ca 2+ ) from i... more Activation of phospholipase C in nonexcitable cells causes the release of calcium (Ca 2+ ) from intracellular stores and activation of Ca 2+ influx by means of Ca 2+ release-activated channels (I CRAC ) in the plasma membrane. The molecular identity and the mechanism of I CRAC channel activation are poorly understood. Using the patch–clamp technique, here we describe the plasma membrane Ca 2+ channels in human carcinoma A431 cells, which can be activated by extracellular UTP, by depletion of intracellular Ca 2+ stores after exposure to the Ca 2+ -pump inhibitor thapsigargin, or by loading the cells with Ca 2+ chelator 1,2-bis(2-aminophenoxy)ethane- N,N,N ′ ,N ′-tetraacetate. The observed channels display the same conductance and gating properties as previously described I min channels, but have significantly lower conductance for monovalent cations than the I CRAC channels. Thus, we concluded that the depletion-activated Ca 2+ current in A431 cells is supported by I CRAC -like (I CR...

Biochimie, 2013

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to neuron death and synapse l... more Alzheimer's disease (AD) is a neurodegenerative disorder that leads to neuron death and synapse loss in the hippocampus and cortex, with consequent cognitive disability and dementia. Mutations in the presenilin-1 (PS1) gene lead to familial Alzheimer's disease (FAD). Here, we report that the expression of FAD-linked PS1 M146V mutant affects store-operated calcium channel activity (Isoc) in human neuroblastoma SKeNeSH cells. Electrophysiological measurements and calcium imaging experiments have revealed the emergent role of calcium sensor STIM2 in the inhibition of calcium release-activated calcium channel activity (Icrac) and enhancement of intracellular Ca 2þ stores content due to PS1 M146V mutant expression. In general, the results of this study suggest that the pathological inhibition of one type of store-operated calcium channels caused by FAD PS1 mutant expression may be accounted for by preceding gain of spontaneous activity of store-operated calcium channels driven by STIM2.

Journal of General Physiology, 2003

Activation of phospholipase C (PLC)-mediated signaling pathways in nonexcitable cells causes the ... more Activation of phospholipase C (PLC)-mediated signaling pathways in nonexcitable cells causes the release of Ca2+ from intracellular Ca2+ stores and activation of Ca2+ influx across the plasma membrane. Two types of Ca2+ channels, highly Ca2+–selective ICRAC and moderately Ca2+–selective ISOC, support store-operated Ca2+ entry process. In previous patch-clamp experiments with a human carcinoma A431 cell line we described store-operated Imin/ICRACL plasma membrane Ca2+ influx channels. In the present paper we use whole-cell and single-channel recordings to further characterize store-operated Ca2+ influx pathways in A431 cells. We discovered that (a) ICRAC and ISOC are present in A431 cells; (b) ICRAC currents are highly selective for divalent cations and fully activate within 150 s after initiation of Ca2+ store depletion; (c) ISOC currents are moderately selective for divalent cations (PBa/PCs = 14.5) and require at least 300 s for full activation; (d) ICRAC and ISOC currents are act...

Cellular Physiology and Biochemistry, 2020

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 I... more This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Биологические мембраны: Журнал мембранной и клеточной биологии, 2019

Наследственная болезнь Альцгеймера-тяжелое нейродегенеративное заболевание, большинство случаев к... more Наследственная болезнь Альцгеймера-тяжелое нейродегенеративное заболевание, большинство случаев которого связано с мутациями в гене белка пресенилина-1 (PS1). В норме PS1 претерпевает расщепление с образованием концевых фрагментов, которые входят в состав γ-секретазного комплекса. Значительная часть мутаций в гене белка PS1 приводит к нарушению его эндопротеолиза и накоплению PS1 в полноразмерной форме. Делеция девятого экзона гена PS1, ассоциированная с болезнью Альцгеймера, приводит к утрате сайта эндопротеолиза, накоплению полноразмерной формы белка. При болезни Альцгеймера наблюдается нарушение кальциевого гомеостаза, в частности, изменение депонирования кальция и, соответственно, дисрегуляция депо-управляемого входа кальция. В данной работе показано, что PS1 с делецией девятого экзона (PS1 ΔE9) и мутантный PS1 D257A, которые не подвергаются протеолитическому расщеплению, накапливались в клетках в полноразмерной форме. Накопление мутантных форм PS1 приводило к увеличению депо-управляемого входа кальция. Экспрессия концевых фрагментов PS1 не влияла на величину депо-управляемого входа кальция. Таким образом, увеличение депо-управляемого кальциевого входа в клеточных моделях наследственной модели болезни Альцгеймера связано исключительно с накоплением полноразмерного PS1 и не зависит от его γ-секретазной активности.

The Journal of General Physiology, 1998

The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+release from intracellular stor... more The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+release from intracellular stores in response to generation of second messenger InsP3. InsP3R was biochemically purified and cloned, and functional properties of native InsP3-gated Ca2+channels were extensively studied. However, further studies of InsP3R are obstructed by the lack of a convenient functional assay of expressed InsP3R activity. To establish a functional assay of recombinant InsP3R activity, transient heterologous expression of neuronal rat InsP3R cDNA (InsP3R-I, SI− SII+ splice variant) in HEK-293 cells was combined with the planar lipid bilayer reconstitution experiments. Recombinant InsP3R retained specific InsP3binding properties (Kd= 60 nM InsP3) and were specifically recognized by anti–InsP3R-I rabbit polyclonal antibody. Density of expressed InsP3R-I was at least 20-fold above endogenous InsP3R background and only 2–3-fold lower than InsP3R density in rat cerebellar microsomes. When incorporated i...

Journal of Biological Chemistry, 2000

1 The abbreviations used are: InsP 3 , inositol 1,4,5-trisphosphate; I CRAC , calcium release-act... more 1 The abbreviations used are: InsP 3 , inositol 1,4,5-trisphosphate; I CRAC , calcium release-activated channel(s); I min , InsP 3-dependent miniature calcium channel(s); InsP 3 R, InsP 3 receptor; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PIP 2 Ab, anti-PIP 2 monoclonal antibody.

Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage... more Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage and diabetic nephropathy. Previous studies demonstrated that TRPC6 channels play a pivotal role in podocyte function and their dysregulation is associated with development of different kidney diseases including nephropathy. It was assumed that activation of TRPC6 channels leads directly to the Ca2+ influx into cells. Another Ca2+ influx pathway, a store-operated Ca2+ entry (SOCE) via ORAI channels, was also shown to be disturbed during the diabetes development. Here, using single channel patch clamp technique, we demonstrated that non-selective cationic TRPC6 channels are sensitive to the Ca2+ store depletion in human podocyte cell line Ab8/13 and in freshly isolated rat glomerular podocytes. Ca2+ imaging indicated the involvement of ORAI and sodium-calcium exchanger (NCX) in Ca2+ entry induced upon store depletion. Ca2+ inflow by NCX is a result of pronounced TRPC6-mediated Na+ influx ...

International Journal of Molecular Sciences

Quinazoline derivatives have various pharmacological activities and are widely used in clinical p... more Quinazoline derivatives have various pharmacological activities and are widely used in clinical practice. Here, we reviewed the proposed mechanisms of the physiological activity of the quinazoline derivative EVP4593 and perspectives for its clinical implication. We summarized the accumulated data about EVP4593 and focused on its activities in different models of Huntington’s disease (HD), including patient-specific iPSCs-based neurons. To make a deeper insight into its neuroprotective role in HD treatment, we discussed the ability of EVP4593 to modulate calcium signaling and reduce the level of the huntingtin protein. Moreover, we described possible protective effects of EVP4593 in other pathologies, such as oncology, cardiovascular diseases and parasite invasion. We hope that comprehensive analyses of the molecular mechanisms of EVP4593 activity will allow for the expansion of the scope of the EVP4593 application.

Neuroscience Bulletin, Oct 14, 2022

Molecular Neurobiology, 2021

Impairment of proteostasis network is one of the characteristic features of many age-related neur... more Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington's disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

International Journal of Molecular Sciences

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeo... more Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry med...

Biochemical and Biophysical Research Communications

International Journal of Molecular Sciences

Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in s... more Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in store-operated Ca2+ entry (SOCE). Ca2+ release through inositol 1,4,5-trisphosphate receptor (IP3R) and subsequent Ca2+ store depletion activate STIM (stromal interaction molecules) proteins, sensors of intraluminal Ca2+, which, in turn, open the Orai channels in plasma membrane. Downstream to this process could be activated TRPC (transient receptor potential-canonical) calcium permeable channels. Using single channel patch-clamp technique we found that a local Ca2+ entry through TRPC1 channels activated endogenous Ca2+-activated chloride channels (CaCCs) with properties similar to Anoctamin6 (TMEM16F). Our data suggest that their outward rectification is based on the dependence from membrane potential of both the channel conductance and the channel activity: (1) The conductance of active CaCCs highly depends on the transmembrane potential (from 3 pS at negative potentials till 60 pS at p...

International Journal of Molecular Sciences, 2021

The actin cytoskeleton of podocytes plays a central role in the functioning of the filtration bar... more The actin cytoskeleton of podocytes plays a central role in the functioning of the filtration barrier in the kidney. Calcium entry into podocytes via TRPC6 (Transient Receptor Potential Canonical 6) channels leads to actin cytoskeleton rearrangement, thereby affecting the filtration barrier. We hypothesized that there is feedback from the cytoskeleton that modulates the activity of TRPC6 channels. Experiments using scanning ion-conductance microscopy demonstrated a change in migration properties in podocyte cell cultures treated with cytochalasin D, a pharmacological agent that disrupts the actin cytoskeleton. Cell-attached patch-clamp experiments revealed that cytochalasin D increases the activity of TRPC6 channels in CHO (Chinese Hamster Ovary) cells overexpressing the channel and in podocytes from freshly isolated glomeruli. Furthermore, it was previously reported that mutation in ACTN4, which encodes α-actinin-4, causes focal segmental glomerulosclerosis and solidifies the actin...

Acta Naturae, 2010

ABSTARCT Store-operated channels are major calcium influx pathways in nonexitable cells. Homer sc... more ABSTARCT Store-operated channels are major calcium influx pathways in nonexitable cells. Homer scaffold proteins are well known for their role in regulating calcium signaling. Here we report on a detailed single-channel level characterization of native store-operated channels regulated by Homer scaffold proteins in A431 carcinoma cells. By applying the single-channel patch-clamp technique, we found that different types of store-operated calcium channels have different sensitivities to Homer proteins.

Acta Naturae, 2014

We have shown that the expression of full-length mutated huntingtin in human neuroblastoma cells ... more We have shown that the expression of full-length mutated huntingtin in human neuroblastoma cells (SK-N-SH) leads to an abnormal increase in calcium entry through store-operated channels. In this paper, the expression of the N-terminal fragment of mutated huntingtin (Htt138Q-1exon) is shown to be enough to provide an actual model for Huntingtons disease. We have shown that Htt138Q-1exon expression causes increased store-operated calcium entry, which is mediated by at least two types of channels in SK-N-SH cells with different reversal potentials. Calcium sensor, STIM1, is required for activation of store-operated calcium entry in these cells. The results provide grounds for considering the proteins responsible for the activation and maintenance of the store-operated calcium entry as promising targets for developing novel therapeutics for neurodegenerative diseases.

Acta Naturae, 2017

Huntingtons disease (HD) is a severe inherited neurodegenerative disorder characterized by motor ... more Huntingtons disease (HD) is a severe inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and mental impairment. At the molecular level, HD is caused by a mutation in the first exon of the gene encoding the huntingtin protein. The mutation results in an expanded polyglutamine tract at the N-terminus of the huntingtin protein, causing the neurodegenerative pathology. Calcium dyshomeostasis is believed to be one of the main causes of the disease, which underlies the great interest in the problem among experts in molecular physiology. Recent studies have focused on the development of animal and insect HD models, as well as patient-specific induced pluripotent stem cells (HD-iPSCs), to simulate the diseases progression. Despite a sesquicentennial history of HD studies, the issues of diagnosis and manifestation of the disease have remained topical. The present review addresses these issues.

Doklady Biological Sciences, 2008

Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections / translated from Russian, 2013

181 Activation of neurotransmitter receptors coupled to G proteins activating phospholipase C in ... more 181 Activation of neurotransmitter receptors coupled to G proteins activating phospholipase C in the plasma membrane (PM) of neuronal cells leads to an increase in the inositol 1,4,5 trisphosphate (IP3) con centration, the activation of inositol 1,4,5 trisphos phate receptor (IP3R), and, consequently, the release of calcium from the lumen of endoplasmic reticulum (ER). The increase in the calcium concentration in the cytoplasm activates ryanodine receptor (RyR), which also leads to release of calcium from ER [1]. Due to decrease in calcium concentration in ER, there are a signal transmission by calcium sensors STIM1 and STIM2 in ER to store operated calcium channels in PM, their activation, and calcium influx into the cell [2]. TRPC proteins (subunits of store operated calcium channels), metabotropic glutamate receptors (mGluR), RyR, and IP3R are the target pro teins specifically binding the adapter protein Homer 1c [3–6]. Oligomers of Homer 1c associated with target proteins form large molecular complexes and establish signal transmission in the area of postsynaptic density of neurons [4]. It has been suggested that adapter pro tein Homer 1c may take part in the regulation of sig naling from neurotransmitter to intracellular stores and store operated calcium channels in neurons.

Proceedings of the National Academy of Sciences, 2001

Activation of phospholipase C in nonexcitable cells causes the release of calcium (Ca 2+ ) from i... more Activation of phospholipase C in nonexcitable cells causes the release of calcium (Ca 2+ ) from intracellular stores and activation of Ca 2+ influx by means of Ca 2+ release-activated channels (I CRAC ) in the plasma membrane. The molecular identity and the mechanism of I CRAC channel activation are poorly understood. Using the patch–clamp technique, here we describe the plasma membrane Ca 2+ channels in human carcinoma A431 cells, which can be activated by extracellular UTP, by depletion of intracellular Ca 2+ stores after exposure to the Ca 2+ -pump inhibitor thapsigargin, or by loading the cells with Ca 2+ chelator 1,2-bis(2-aminophenoxy)ethane- N,N,N ′ ,N ′-tetraacetate. The observed channels display the same conductance and gating properties as previously described I min channels, but have significantly lower conductance for monovalent cations than the I CRAC channels. Thus, we concluded that the depletion-activated Ca 2+ current in A431 cells is supported by I CRAC -like (I CR...

Biochimie, 2013

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to neuron death and synapse l... more Alzheimer's disease (AD) is a neurodegenerative disorder that leads to neuron death and synapse loss in the hippocampus and cortex, with consequent cognitive disability and dementia. Mutations in the presenilin-1 (PS1) gene lead to familial Alzheimer's disease (FAD). Here, we report that the expression of FAD-linked PS1 M146V mutant affects store-operated calcium channel activity (Isoc) in human neuroblastoma SKeNeSH cells. Electrophysiological measurements and calcium imaging experiments have revealed the emergent role of calcium sensor STIM2 in the inhibition of calcium release-activated calcium channel activity (Icrac) and enhancement of intracellular Ca 2þ stores content due to PS1 M146V mutant expression. In general, the results of this study suggest that the pathological inhibition of one type of store-operated calcium channels caused by FAD PS1 mutant expression may be accounted for by preceding gain of spontaneous activity of store-operated calcium channels driven by STIM2.

Journal of General Physiology, 2003

Activation of phospholipase C (PLC)-mediated signaling pathways in nonexcitable cells causes the ... more Activation of phospholipase C (PLC)-mediated signaling pathways in nonexcitable cells causes the release of Ca2+ from intracellular Ca2+ stores and activation of Ca2+ influx across the plasma membrane. Two types of Ca2+ channels, highly Ca2+–selective ICRAC and moderately Ca2+–selective ISOC, support store-operated Ca2+ entry process. In previous patch-clamp experiments with a human carcinoma A431 cell line we described store-operated Imin/ICRACL plasma membrane Ca2+ influx channels. In the present paper we use whole-cell and single-channel recordings to further characterize store-operated Ca2+ influx pathways in A431 cells. We discovered that (a) ICRAC and ISOC are present in A431 cells; (b) ICRAC currents are highly selective for divalent cations and fully activate within 150 s after initiation of Ca2+ store depletion; (c) ISOC currents are moderately selective for divalent cations (PBa/PCs = 14.5) and require at least 300 s for full activation; (d) ICRAC and ISOC currents are act...

Cellular Physiology and Biochemistry, 2020

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 I... more This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Биологические мембраны: Журнал мембранной и клеточной биологии, 2019

Наследственная болезнь Альцгеймера-тяжелое нейродегенеративное заболевание, большинство случаев к... more Наследственная болезнь Альцгеймера-тяжелое нейродегенеративное заболевание, большинство случаев которого связано с мутациями в гене белка пресенилина-1 (PS1). В норме PS1 претерпевает расщепление с образованием концевых фрагментов, которые входят в состав γ-секретазного комплекса. Значительная часть мутаций в гене белка PS1 приводит к нарушению его эндопротеолиза и накоплению PS1 в полноразмерной форме. Делеция девятого экзона гена PS1, ассоциированная с болезнью Альцгеймера, приводит к утрате сайта эндопротеолиза, накоплению полноразмерной формы белка. При болезни Альцгеймера наблюдается нарушение кальциевого гомеостаза, в частности, изменение депонирования кальция и, соответственно, дисрегуляция депо-управляемого входа кальция. В данной работе показано, что PS1 с делецией девятого экзона (PS1 ΔE9) и мутантный PS1 D257A, которые не подвергаются протеолитическому расщеплению, накапливались в клетках в полноразмерной форме. Накопление мутантных форм PS1 приводило к увеличению депо-управляемого входа кальция. Экспрессия концевых фрагментов PS1 не влияла на величину депо-управляемого входа кальция. Таким образом, увеличение депо-управляемого кальциевого входа в клеточных моделях наследственной модели болезни Альцгеймера связано исключительно с накоплением полноразмерного PS1 и не зависит от его γ-секретазной активности.

The Journal of General Physiology, 1998

The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+release from intracellular stor... more The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+release from intracellular stores in response to generation of second messenger InsP3. InsP3R was biochemically purified and cloned, and functional properties of native InsP3-gated Ca2+channels were extensively studied. However, further studies of InsP3R are obstructed by the lack of a convenient functional assay of expressed InsP3R activity. To establish a functional assay of recombinant InsP3R activity, transient heterologous expression of neuronal rat InsP3R cDNA (InsP3R-I, SI− SII+ splice variant) in HEK-293 cells was combined with the planar lipid bilayer reconstitution experiments. Recombinant InsP3R retained specific InsP3binding properties (Kd= 60 nM InsP3) and were specifically recognized by anti–InsP3R-I rabbit polyclonal antibody. Density of expressed InsP3R-I was at least 20-fold above endogenous InsP3R background and only 2–3-fold lower than InsP3R density in rat cerebellar microsomes. When incorporated i...

Journal of Biological Chemistry, 2000

1 The abbreviations used are: InsP 3 , inositol 1,4,5-trisphosphate; I CRAC , calcium release-act... more 1 The abbreviations used are: InsP 3 , inositol 1,4,5-trisphosphate; I CRAC , calcium release-activated channel(s); I min , InsP 3-dependent miniature calcium channel(s); InsP 3 R, InsP 3 receptor; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PIP 2 Ab, anti-PIP 2 monoclonal antibody.