MECHANISM OF CALCIUM HOMEOSTASIS AND ITS ROLE IN NEURODEGENERATIVE PROCESSES

Аннотация

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 therapeuticstrategies. Keywords:Calcium (Ca²⁺), calcium channels, calcium transport, NMDA receptors, polyphenols. Calcium (Ca²⁺) is one of the most universal ions in the body, 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 pavetheway for effectivetherapeutic 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 withits 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 www.wordlyknowledge.uz ILMIYMETODIK JURNAL JOURNAL OFIQRO –ЖУРНАЛ ИҚРО –IQRO JURNALI –volume 14,issue01,2025 ISSN:2181-4341, IMPACT FACTOR( RESEARCH BIB )–7,245,SJIF–5,431 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 t