JOURNAL OF IQRO – ЖУРНАЛ ИҚРО – IQRO JURNALI – volume 14, issue 01, 2025
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Mukhtorov Alisher A., Manopova Maftuna I.
National University of Uzbekistan named after Mirzo Ulug’bek
Department of Human and Animal Physiology
Email: alik_evros@mail.ru
MECHANISM OF CALCIUM HOMEOSTASIS AND ITS ROLE IN
NEURODEGENERATIVE PROCESSES
Abstract:
Calcium (Ca²⁺) plays a key role in regulating neuronal activity, plasticity, and cell
survival in the brain. Its transport across the membrane occurs through voltage-gated calcium
channels, ionotropic and metabotropic receptors, calcium pumps, and exchangers. Disruptions in
calcium homeostasis are associated with neurodegenerative diseases such as Alzheimer's and
Parkinson's disease. Bioactive compounds, including polyphenols, can modulate calcium
transport, exerting neuroprotective effects. Studying these mechanisms opens new perspectives
for developing therapeutic strategies.
Keywords:
Calcium (Ca²⁺), calcium channels, calcium transport, NMDA receptors, polyphenols.
Calcium (Ca²⁺) is one of the most universal ions in the div, playing a crucial role in regulating
numerous processes, particularly in neurons. These cells have a remarkable ability to generate
and transmit signals, with calcium serving as an essential mediator in regulating their activity,
plasticity, and survival. The intracellular calcium balance is maintained with high precision, as
even minor fluctuations in its concentration can significantly alter the functioning of the nervous
system. Disruptions in calcium homeostasis are linked to severe neurological disorders,
including Alzheimer's disease, Parkinson's disease, stroke, and epilepsy. Understanding the
mechanisms governing Ca²⁺ transport across the cell membrane is of fundamental importance
and could pave the way for effective therapeutic strategies.
Studying the mechanisms of calcium transport across cell membranes is a crucial task in modern
neurobiology. Understanding the fine regulation of calcium balance in neurons will not only
deepen our knowledge of brain function but also aid in developing new approaches for treating
disorders associated with its disruption.
It is well known that calcium ion influx into nerve terminals through voltage-gated calcium
channels triggers a cascade of reactions leading to neurotransmitter exocytosis, thereby ensuring
excitation transmission through synaptic contacts [1]. Additionally, calcium-activated potassium
channels play a vital role in reducing neuronal excitability after activation, thereby regulating
action potential frequency and preventing excessive neuronal activity. These channels are crucial
in modulating brain states such as sleep and in the pathogenesis of epileptic seizures. During
learning and long-term memory formation, significant changes in the expression of calcium-
activated potassium channels are observed, presumably affecting the excitability of individual
neurons and neural networks [2].
One study indicates that Ca²⁺ influx through NMDA receptors activates CaM kinase II (CaMKII),
which subsequently alters receptor expression, strengthening neuronal connections (a basis for
memory and learning) [3]. According to another study, the "calcium hypothesis" postulates that
atrophic and degenerative processes in neurons of patients with Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis, Huntington's disease, and spinocerebellar ataxias are
JOURNAL OF IQRO – ЖУРНАЛ ИҚРО – IQRO JURNALI – volume 14, issue 01, 2025
ISSN: 2181-4341, IMPACT FACTOR ( RESEARCH BIB ) – 7,245, SJIF – 5,431
ILMIY METODIK JURNAL
accompanied by changes in calcium homeostasis. Moreover, this hypothesis suggests that
calcium signaling disturbances are among the key and early processes leading to disease
development [4]. There is also evidence that Ca²⁺ entry into the cell leads to phosphorylation of
CREB via activation of calcium/calmodulin-dependent protein kinases, thereby regulating gene
expression involved in neuroplasticity [5].
Calcium transport across neuronal membranes occurs via several key mechanisms: voltage-gated
calcium channels (VGCCs), ionotropic and metabotropic receptors, calcium pumps, and
exchangers. Voltage-gated calcium channels open in response to membrane potential changes,
allowing calcium ions to enter the cell. They play a critical role in initiating synaptic
transmission and other calcium-dependent processes [6]. NMDA receptors are ionotropic
glutamate receptors activated by glutamate and a co-agonist (glycine or D-serine). Their
activation permits calcium influx into neurons, contributing to synaptic plasticity and signal
transmission [7]. AMPA receptors, also ionotropic glutamate receptors, mediate fast synaptic
responses. Their permeability to Ca²⁺ depends on their subunit composition; some allow Ca²⁺
influx, affecting synaptic plasticity [8]. Kainate receptors, another type of ionotropic receptor,
are activated by glutamate or kainic acid and participate in regulating neuronal excitability and
neurotransmission. Their permeability to Ca²⁺ also depends on their specific subunit composition
[9].
Calcium pumps and exchangers include plasma membrane calcium ATPases (PMCA),
sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA), and sodium-calcium
exchangers (NCX). These mechanisms remove excess calcium from the cytoplasm, maintaining
homeostasis and preventing calcium overload [10].
Calcium transport in neurons is a tightly regulated process ensuring synaptic transmission,
plasticity, and neuroprotection. Bioactive compounds (BACs) can alter this balance by
modulating the activity of calcium channels, receptors, pumps, and exchangers. Their effects can
be either protective, promoting neuroprotection, or pathological, leading to calcium homeostasis
disturbances. Several compounds can block VGCCs, reducing calcium ion influx into cells. For
instance, nifedipine, a dihydropyridine, blocks L-type VGCCs, thereby decreasing calcium
current [11]. Similarly, pharmacological agents such as nimodipine and verapamil act as calcium
channel antagonists and are used to reduce intracellular calcium influx, beneficial in treating
various neurological conditions [12,13].
VGCC activity can also be influenced physiologically by altering extracellular potassium ion
concentrations. Increased extracellular K⁺ concentration raises the probability of calcium channel
opening, enhancing Ca²⁺ entry into the cell [14]. Specific agonists and antagonists can enhance
or suppress ionotropic receptor activity. For example, ketamine is an NMDA receptor antagonist
used in medicine as an anesthetic and antidepressant [15].
There is also evidence of the neuroprotective properties of certain natural bioactive compounds.
One study suggests that a flavonoid-rich Ginkgo biloba extract positively affects memory,
learning, and concentration by upregulating AMPA, calcium, and chloride channels [16].
Glutamate-induced neuronal damage was inhibited by the polyphenol resveratrol, which
prevented activation of NMDA/AMPA/KA receptors and intracellular Ca²⁺ influx [17].
Additionally, recent studies indicate that some plant-derived polyphenols influence intrinsic and
extrinsic blood coagulation pathways in rats with an Alzheimer's disease model. This is
attributed to their potential ability to block plasma membrane calcium channels, thereby
preventing calcium entry into platelets and reducing free Ca²⁺ ion concentration [18].
JOURNAL OF IQRO – ЖУРНАЛ ИҚРО – IQRO JURNALI – volume 14, issue 01, 2025
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Another study investigating potential neuroprotective agents for Alzheimer's disease found that
certain plant-derived polyphenols positively regulated ion channel opening through interaction
with NMDA receptors, thereby influencing intracellular Ca²⁺ concentration [19].
Moreover, gingerol, the main bioactive component of ginger, has attracted significant attention
as a potential therapeutic agent for preventing and treating various disorders, including
cardiovascular diseases, diabetes, metabolic syndrome, and neurodegenerative diseases [20].
Ginger extract affects energy metabolism through AMPK/SIRT1 regulation involving Ca²⁺
homeostasis, making it potentially useful in treating obesity and related metabolic complications
[21].
Additionally, strong stimulation of SERCA2 activity by ellagic acid (a derivative of gallic acid
widely found in berries, fruits, and nuts) has been reported [22]. Other potent SERCA activators
include natural compounds such as luteolin, myricetin, and baicalein [23].
Disruptions in calcium homeostasis contribute to the development of various neurodegenerative
conditions, from neurological disorders to severe diseases such as Alzheimer's disease,
Parkinson's disease, Huntington's disease, and neuronal death following brain ischemia and
stroke [24].
Conclusion:
Calcium homeostasis plays a critical role in regulating neuronal activity, plasticity, and brain cell
survival. Disruptions in Ca²⁺ transport can lead to neurodegenerative diseases, making research
in this area highly relevant. Maintaining intracellular calcium balance through calcium channels,
receptors, pumps, and exchangers is essential. Modern studies indicate that bioactive compounds
can modulate calcium channel activity, exerting neuroprotective effects. This opens new
perspectives for developing innovative therapeutic strategies against neurodegeneration.
References
1. Features of Calcium Regulation of Mediator Secretion Kinetics in Neuromuscular Synapses
of Cold-Blooded and Warm-Blooded Animals" / A. N. Tsentsevitsky, V. F. Khuzakhmetova, A.
L. Vasin [et al.] // Biological Membranes. – 2015. – Т. 32, № 5-6. – С. 310. – DOI
10.7868/S0233475515050187. – EDN UVEVUD.
2. Nikitin, E. S., Balaban, P. M. Diversity and Functional Features of Calcium-Dependent
Potassium Channels Determining Their Role in Neuronal Plasticity of the Brain //
Journal of
Higher Nervous Activity named after I. P. Pavlov.
– 2021. – Т. 71, № 2. – С. 237-243. – DOI
10.31857/S0044467721020088. – EDN HBUVWL.
3.
Gardoni, F., Caputi, A., Cimino, M., Pastorino, L., Cattabeni, F., & Di Luca, M. (1998).
Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA
receptor in postsynaptic densities.
Journal of neurochemistry
,
71
(4), 1733–1741.
https://doi.org/10.1046/j.1471-4159.1998.71041733.x
4. Bezprozvanny, I. B. The Calcium Signaling System in Neurodegeneration. // Acta Naturae.
2010.
№1.
URL:
https://cyberleninka.ru/article/n/sistema-kaltsievoy-signalizatsii-pri-
neyrodegeneratsii.
5.
Sheng, M., Thompson, M. A., & Greenberg, M. E. (1991). CREB: a Ca(2+)-regulated
transcription factor phosphorylated by calmodulin-dependent kinases.
Science (New York,
N.Y.)
,
252
(5011), 1427–1430. https://doi.org/10.1126/science.1646483+
6. Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R., & Fox, A. P. (1988). Multiple
types of neuronal calcium channels and their selective modulation. Trends in neurosciences,
11(10), 431–438.
JOURNAL OF IQRO – ЖУРНАЛ ИҚРО – IQRO JURNALI – volume 14, issue 01, 2025
ISSN: 2181-4341, IMPACT FACTOR ( RESEARCH BIB ) – 7,245, SJIF – 5,431
ILMIY METODIK JURNAL
7. Каспер Б. Хансен , Фэн Йи , Райли Э. Першик , Хиро Фурукава , Лонни П. Уоллмут ,
Аласдер Дж. Гибб , Стивен Ф. Трейнелис; Структура, функции и аллостерическая
модуляция рецепторов NMDA. J Gen Physiol 6 августа 2018 г.; 150 (8): 1081–1105. дои:
https://doi.org/10.1085/jgp.201812032
8. Тихонов, Д. Б. Каналоблокаторы ионотропных рецепторов глутамата / Д. Б. Тихонов
// Российский физиологический журнал им. И.М. Сеченова. – 2021. – Т. 107, № 4-5. – С.
403-416. – DOI 10.31857/S0869813921040142. – EDN XCSSYU.
9. James E Huettner, Kainate receptors and synaptic transmission, Progress in Neurobiology,
Volume 70, Issue 5, 2003, Pages 387-407, ISSN 0301-0082, https://doi.org/10.1016/S0301-
0082(03)00122-9.
10. Smolyaninova, L. V., Shiyan, A. A., Maksimov, G. V., Orlov, S. N. Contribution of
Monovalent (Na+ and K+) and Divalent (Ca2+) Ions to the Mechanisms of Synaptic Plasticity //
Biological Membranes.
– 2020. – Т. 37, № 6. – С. 403-425. – DOI
10.31857/S0233475520060067. – EDN YBXCAA.
11. Leonard, R. G., & Talbert, R. L. (1982). Calcium-channel blocking agents. Clinical
pharmacy, 1(1), 17–33.
12. Langham, J., Goldfrad, C., Teasdale, G., Shaw, D., & Rowan, K. (2003). Calcium channel
blockers for acute traumatic brain injury. The Cochrane database of systematic reviews, (4),
CD000565. https://doi.org/10.1002/14651858.CD000565
13. Li, W., & Shi, G. (2019). How CaV1.2-bound verapamil blocks Ca2+ influx into
cardiomyocyte:
Atomic
level
views.
Pharmacological
research,
139,
153–157.
https://doi.org/10.1016/j.phrs.2018.11.017
14. Khaziev E.F., Balashova D.V., Tsentsevitsky A.N., Bukharaeva E.A., Samigullin D.V.
Calcium Transient and Mediator Release in Different Parts of the Frog Nerve Ending on the
Change of Conditions of Calcium Ions Entry. Russian Journal of Physiology. 105(10): 1262–
1270. DOI: 10.1134/S0869813919100030
15. Dergachev V.D., Yakovleva E.E., Bychkov E.R., Piotrovskiy L.B., Shabanov P.D. Role of
glutamate receptor complex in the organism. Ligands of NMDA receptors in neurodegenerative
processes – a modern state of the problem // Reviews on Clinical Pharmacology and Drug
Therapy. - 2022. - Vol. 20. - N. 1. - P. 17-28. doi: 10.17816/RCF20117-28
16. Watanabe C. M. H., Wolffram S., Ader P., Rimbach G., Packer L., Maguire J. J., Schultz P.
G., and Gohil K., The in vivo neuromodulatory effects of the herbal medicine Ginkgo biloba,
Proceedings of the National Academy of Sciences of the United States of America. (2001) 98, no.
12, 6577–6580, 2-s2.0-0035811001,
https://doi.org/10.1073/pnas.111126298
17. Quincozes-Santos, A., Bobermin, L. D., Tramontina, A. C., Wartchow, K. M., Tagliari, B.,
Souza, D. O., Wyse, A. T., & Gonçalves, C. A. (2014). Oxidative stress mediated by NMDA,
AMPA/KA channels in acute hippocampal slices: neuroprotective effect of resveratrol.
Toxicology in vitro : an international journal published in association with BIBRA, 28(4), 544–
551.
https://doi.org/10.1016/j.tiv.2013.12.021
18. Numonjonovich, K. N. ., Baxtiyarovich, K. I. ., Ugli, D. J. I. ., Salimovich, K. S. ., Ugli, M.
A. A. ., Ugli, O. M. M. ., Erkinovich, N. K. ., Amindjanovna, M. Z. ., Abdullayevna, S. G. ., &
Nurillayevich, R. R. . (2024). Еffесt of Pоlyphеnоls on Сhаngеs in thе Hеmоstаtiс Systеm of
Blооd Plаsmа in Hеаlthy and Mоdеl Rаts with Аlzhеimеr’s Disеаsе.
Trends in Sciences
,
21
(9),
8081.
https://doi.org/10.48048/tis.2024.8081
19. Nozim N. Khoshimov, Alisher A. Mukhtorov, Kabil E. Nasirov, Rakhmatilla N. R;akhimov,
Rahmatjon R. Mamadaminov. Effects of Polyphenols on changes in the transport of Ca2+
NMDA-receptors under the influence of L-glutamate. Research Journal of Pharmacy and
Technology 2023; 16(3):1205-3. doi: 10.52711/0974-360X.2023.00200
20. Arcusa, R.; Villaño, D.; Marhuenda, J.; Cano, M.; Cerdà, B.; Zafrilla, P. Potential Role of
Ginger (Zingiber Officinale Roscoe) in the Prevention of Neurodegenerative Diseases. Front.
Nutr. 2022, 9, 809621.
JOURNAL OF IQRO – ЖУРНАЛ ИҚРО – IQRO JURNALI – volume 14, issue 01, 2025
ISSN: 2181-4341, IMPACT FACTOR ( RESEARCH BIB ) – 7,245, SJIF – 5,431
ILMIY METODIK JURNAL
21. Lee, G.H.; Peng, C.; Jeong, S.Y.; Park, S.A.; Lee, H.Y.; Hoang, T.H.; Kim, J.; Chae, H.J.
Ginger Extract Controls MTOR-SREBP1-ER Stress-Mitochondria Dysfunction through AMPK
Activation in Obesity Model. J. Funct. Foods 2021, 87, 1–9.
22. Namekata, I.; Hamaguchi, S.; Wakasugi, Y.; Ohhara, M.; Hirota, Y.; Tanaka, H. Ellagic
Acid and Gingerol, Activators of the Sarco-Endoplasmic Reticulum Ca2+-ATPase, Ameliorate
Diabetes Mellitus-Induced Diastolic Dysfunction in Isolated Murine Ventricular Myocardia. Eur.
J. Pharmacol. 2013, 706, 48–55.
23. Viskupicova, J., & Rezbarikova, P. (2022). Natural Polyphenols as SERCA Activators: Role
in the Endoplasmic Reticulum Stress-Related Diseases. Molecules (Basel, Switzerland), 27(16),
5095.
https://doi.org/10.3390/molecules27165095
24. Zündorf, G., & Reiser, G. Calcium dysregulation and homeostasis of neural calcium in the
molecular mechanisms of neurodegenerative diseases provide multiple targets for
neuroprotection. Antioxidants & redox signaling, 2011,14(7), 1275–1288
