Trends Sci. 2026; 23(4): 12261

Calcium Signaling Pathways in Physiological Regulation and Disease Development: A Comprehensive Review

Aswin Rafif Khairullah^1, , Dea Anita Ariani Kurniasih^2, , Ilma Fauziah Maruf^3, ,

Bima Putra Pratama^4, , Mohammad Sukmanadi^5,*, , Arif Nur Muhammad Ansori^6,7,8, , Imam Mustofa^9, , Bantari Wisynu Kusuma Wardhani^3, , Riza Zainuddin Ahmad^1, ,

Eny Martindah^1, , Sri Mulyati^9, , Wita Yulianti^10, , Abdul Hadi Furqoni^11, ,

Saifur Rehman^12, , Syahputra Wibowo^13, and Fadhila Utari^3,

¹Research Center for Veterinary Science, National Research and Innovation Agency (BRIN),

West Java 16911, Indonesia

²Research Center for Public Health and Nutrition, National Research and Innovation Agency (BRIN),

West Java 16911, Indonesia

³Research Center for Pharmaceutical Ingredients and Traditional Medicine,

National Research and Innovation Agency (BRIN), Bogor, West Java 16911, Indonesia

⁴Research Center for Process Technology, National Research and Innovation Agency (BRIN), Banten 15314, Indonesia

⁵Division of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Universitas Airlangga, Kampus C Mulyorejo, East Java 60115, Indonesia

⁶Postgraduate School, Universitas Airlangga, Kampus B Dharmawangsa, East Java 60286, Indonesia

⁷Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Uttarakhand 248007, India

⁸Medical Biotechnology Research Group, Virtual Research Center for Bioinformatics and Biotechnology,

East Java 60493, Indonesia

⁹Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Kampus C Mulyorejo,

East Java 60115, Indonesia

¹⁰Research Center for Biota Systems, National Research and Innovation Agency (BRIN), West Java 16911, Indonesia

¹¹Center for Biomedical Research, National Research and Innovation Agency (BRIN), West Java 16911, Indonesia

¹²Department of Pathobiology, Faculty of Veterinary and Animal Sciences, Gomal University,

Dera Ismail Khan 27000, Pakistan

¹³Eijkman Research Center for Molecular Biology, National Research and Innovation Agency (BRIN),

West Java 16911, Indonesia

(^*Corresponding author’s e-mail: [email protected])

Received: 13 October 2025, Revised: 24 October 2025, Accepted: 4 December 2025, Published: 1 January 2026

Abstract

Calcium ions (Ca²⁺) are universal signaling molecules that play a central role in physiological processes, including muscle contraction, hormone secretion, gene regulation, energy metabolism, and neurotransmission. This review aims to integrate the SOCE-MCU-CaM axes to provide a systems-level view of Ca²⁺ regulation from the plasma membrane to the ER/SR, mitochondria, and nucleus in physiology and pathology. The Ca²⁺ signaling pathway encompasses ion transport by Ca²⁺ pumps and Na⁺/Ca²⁺ exchangers, ion flow through plasma-membrane channels and the endoplasmic/sarcoplasmic reticulum (ER/SR), and interactions with binding proteins such as calcineurin and calmodulin (CaM), which trigger downstream programs including NFAT, CREB, and MAPK. Maintenance of cytosolic and mitochondrial Ca²⁺ homeostasis depends on pathways such as the mitochondrial calcium uniporter (MCU) and store-operated calcium entry (SOCE) via STIM1/Orai1; their coordinated action links Ca²⁺ transients to metabolism and gene control. Dysregulation of Ca²⁺ signaling contributes to chronic diseases, including neurodegeneration (Alzheimer’s, Parkinson’s), cardiovascular disease (heart failure, arrhythmia, hypertension), cancer (breast, lung, colorectal), and metabolic/endocrine disorders (diabetes and insulin resistance). Unchecked Ca²⁺ accumulation or pathway imbalance promotes oxidative stress, apoptotic activation, impaired energy metabolism, and cellular dysfunction, while mutations in Ca²⁺-related genes alter cardiac contractility and other physiological regulation. Therapeutic approaches include Ca²⁺-channel modulation, targeting STIM1, Orai1, and MCU, and epigenetic strategies that leverage Ca²⁺’s influence on gene expression, with the goal of restoring network-level Ca²⁺ equilibrium and improving cell function. A clearer understanding of Ca²⁺ mechanisms and pathway cross-talk will support the development of more precise and effective interventions.

Keywords: Calcium signaling, Physiology, Pathology, Targeted therapy, Disease

Introduction

Calcium ion (Ca²⁺) is a universal signaling molecule that has a central role in regulating various cellular physiological processes [1]. Ca²⁺ functions as a second messenger, converting both internal and external stimuli into certain physiological and biochemical reactions, such as energy metabolism, hormone release, muscle contraction, and gene transcription [2]. Rapid and regulated changes in intracellular Ca²⁺ concentrations enable cells to adjust their biological activity in response to changes in the environment, preserving organ function and homeostasis [3]. The ability of calcium to create intricate signaling patterns - pulsatile, oscillatory, and spatial - each of which has distinct functional implications in cell regulation. This feature makes it unique as a signaling mediator [4].

Apart from its function in healthy physiology, calcium signaling also plays a part in a number of pathogenic processes. Ca²⁺ dysfunction or dysregulation can trigger or worsen chronic disease conditions, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s, cardiovascular diseases such as arrhythmias and heart failure, and metabolic disorders such as diabetes mellitus [5-8]. At the molecular level, these illnesses are frequently linked to alterations in the expression or function of Ca²⁺-handling proteins (ion channels, pumps, exchangers), Ca²⁺-binding proteins (e.g., calmodulin), and Ca²⁺-regulated enzymes (e.g., calcineurin) [9]. These alterations may result in a dysregulation of Ca²⁺ signaling, which impacts apoptosis, differentiation, proliferation, and other cellular processes, ultimately leading to the advancement of the disease [10].

Complex mechanisms that incorporate several Ca²⁺ sources and sensors are part of the calcium signaling cascade. Ca²⁺ is released or absorbed by the

endoplasmic reticulum (ER) and mitochondria, which act as internal reservoirs in response to physiological demands [11]. Additionally, Ca²⁺ enters through plasma membrane pathways such as store-operated Ca²⁺ entry (SOCE) and voltage-gated calcium channels (VGCCs), which enable cells to react to changes in the extracellular environment [12]. The Na⁺/Ca²⁺ exchanger and Ca²⁺ pumps like plasma membrane Ca²⁺-ATPase (PMCA) and sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) dynamically maintain Ca²⁺ homeostasis [13]. Cells are able to precisely control Ca²⁺ fluctuations through the combination of these several pathways, maintaining appropriate physiological responses [14].

Ca²⁺ plays a role as a signaling mediator that extends beyond quick reactions; it also affects long-term control by triggering downstream signal transduction pathways [15]. A range of molecular targets, such as kinases, phosphatases, and transcription factors like Nuclear Factor of Activated T-cells (NFAT) and cAMP Response Element-Binding protein (CREB), interact with calcium-binding proteins like calmodulin to control gene expression and cell activity in a particular way [16]. Chronic cellular dysfunction can result from anomalies in this pathway, which explains how Ca²⁺ can act as a connection between environmental changes and long-term cellular adaptation [17].

This review aims to provide a comprehensive overview of the calcium signaling pathway, focusing on its regulatory mechanisms, physiological roles, and association with the pathology of various diseases. The primary issues discussed are how disruption in calcium signaling affects the course of disease and how a better knowledge of this route could lead to the creation of more targeted treatment approaches. As a result, this paper offers a conceptual framework that can be applied to future studies and the creation of therapeutic measures that target the modification of Ca²⁺ signals. In particular, this review integrates the SOCE–MCU–CaM axes across the plasma membrane, ER/SR, mitochondria, and nucleus to address the current gap in compartment-spanning perspectives.

Data collection method

This review adopts a narrative, problem-focused search and synthesis strategy. Biblio­graphic searches were performed in PubMed/MEDLINE, Scopus, Web of Science, and Embase to identify publications from 1 January 2000 through 13 October 2025, using controlled vocabulary and free-text terms related to calcium signaling (e.g., “calcium signaling”, “store-operated calcium entry”, STIM1, Orai1, voltage-gated calcium channels, SERCA, PMCA, MCU, calmodulin [CaM], calcineurin, NFAT, CaMK) combined with disease terms (e.g., neurodegeneration, cardiac remodeling/arrhythmia, cancer, endocrine/metabolic dysfunction). Reference lists of sentinel articles were hand-searched to capture additional records. Inclusion criteria encompassed peer-reviewed mechanistic or disease-focused studies and reviews interrogating SOCE, VGCCs, SERCA/PMCA, the MCU complex, or CaM-dependent effectors in human, animal, or primary cell models; single case reports, non-mechanistic commentaries, and off-topic items were excluded. Titles and abstracts underwent screening followed by full-text appraisal; for each eligible study, we extracted variables on signaling nodes, experimental models and assays, principal mechanistic findings, disease context, and therapeutic leads, then synthesized them thematically along SOCE–MCU–CaM axes across organ systems. Formal risk-of-bias scoring was not performed given the narrative scope of this review; evidence weighting emphasized methodological rigor, reproducibility across models, and translational relevance.

Calcium signaling basics

Calcium signaling is a fundamental mechanism that allows cells to respond dynamically and specifically to internal and external stimuli. Numerous sources and regulatory mechanisms, such as the endoplasmic reticulum, mitochondria, membrane ion channels, calcium pumps, and exchangers, carefully control the intracellular Ca²⁺ ion concentration. Calcium-binding proteins like calcineurin and calmodulin (CaM) further convert these Ca²⁺ dynamics into physiological responses by activating downstream signaling pathways including cAMP Response Element-Binding protein (CREB), Nuclear Factor of Activated T-cells (NFAT), and Mitogen-Activated Protein Kinase (MAPK), which in turn coordinates a number of critical cellular functions.

Sources and regulation of Ca²⁺

The concentration of Ca²⁺ in the cytosol is kept at a very low level, usually around 100 nM, to enable quick changes in response to stimuli [18]. These ions are crucial signaling mediators. Intracellular Ca²⁺ homeostasis is achieved through a complex coordination between internal reserves, flux from the extracellular environment, and active transport systems [19].

The endoplasmic reticulum (ER) functions as the main reservoir of intracellular Ca²⁺ [20]. The ER stores these ions, which are then released in response to physiological cues via certain channels such the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP₃R) [21]. Additionally, mitochondria serve as crucial buffers, receiving calcium ions through the mitochondrial Ca²⁺ uniporter (MCU) and releasing them to facilitate apoptotic control and energy consumption [22]. These 2 organelles enable cells to control Ca²⁺ fluctuations in a specific spatial and temporal manner, leading to a precise cellular response [23].

Ion channels in the plasma membrane allow Ca²⁺ from the extracellular environment to enter, which is crucial in addition to internal reserves [24]. The ability to react quickly to changes in the environment is made possible by channels such SOCCs and VGCCs [25]. Ca²⁺-binding proteins, including calmodulin, interpret the brief rise in cytosolic Ca²⁺ concentration caused by channel activation to initiate downstream signaling cascades [26].

Maintenance of Ca²⁺ homeostasis depends not only on passive flux through the channels, but also through active transport mechanisms [27]. Ca²⁺ pumps, like the plasma membrane Ca²⁺-ATPase (PMCA) and the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), constantly transport Ca²⁺ from the cytosol to the ER or out of the cell, preserving a low basal concentration in the cytosol [28]. Furthermore, the Na⁺/Ca²⁺ exchanger uses the sodium gradient to balance the Ca²⁺ concentration, promoting signal renewal and avoiding the buildup of potentially harmful Ca²⁺ [29].

Cells are able to produce dynamic and localized Ca²⁺ signals by the integration of internal reserves, external fluxes, and pump and exchanger activity [30]. This method highlights the significance of appropriate regulation to prevent dysfunction and pathology while explaining how Ca²⁺ can cause a range of physiological responses, from cell proliferation and neural signal transduction to muscular contraction and hormone release [31].

Ca²⁺ signal transduction mechanism

Cells must be able to convert variations in Ca²⁺ content into particular biological reactions in order for calcium signal transduction to occur [9]. Calmodulin (CaM) and other calcium-binding proteins are essential to this process. The EF-hand domain of this protein undergoes a conformational shift when calmodulin binds Ca²⁺, activating several downstream effectors [32]. The Ca²⁺-CaM complex activates calcineurin, a serine/threonine phosphatase, which is one of CaM’s primary targets [33]. The transcription factor NFAT can enter the cell nucleus and affect the expression of genes that govern immunological responses, differentiation, and proliferation when calcineurin activation dephosphorylates it [34].

Along with the CaM-calcineurin route, Ca²⁺ also triggers the activation of several additional transcription factors and kinases, such as CREB and MAPK [35]. Changes in Ca²⁺ can activate MAPK, which can set off a cascade of phosphorylations that control cell division, growth, and death [36]. On the other hand, CREB activation through Ca²⁺-dependent kinases permits control of gene expression involved in memory, metabolic adaptability, and synaptic plasticity [37].

Changes in Ca²⁺ concentration that take place in cellular microdomains can elicit distinct reactions from global changes due to the spatial and temporal specificity of the Ca²⁺ signal transduction pathway [20]. For instance, distinct signaling pathways may be triggered by local Ca²⁺ release close to neuronal synapses as opposed to Ca²⁺ release across the cytoplasm [38]. Cells can precisely customize their responses to physiological stimuli thanks to the intricate integration of these several pathways, which also explains how dysregulation of these pathways can result in a range of disease disorders [39]. As shown in Figure 1, cellular Ca²⁺ homeostasis emerges from membrane influx (VGCC, SOCE/STIM1-Orai1), ER release–reuptake (IP₃R/RyR, SERCA), extrusion (PMCA/NCX), and mitochondrial transport (MCU/NCLX), with decoding via CaM–calcineurin/NFAT and CaMK-CREB axes.

Figure 1 Cellular Ca²⁺ homeostasis.

Major calcium signaling pathways

The major calcium signaling pathways consist of mechanisms that allow cells to precisely regulate the flow and distribution of Ca²⁺, both in the cytosol and internal organelles. The maintenance of calcium homeostasis, the coordination of numerous physiological processes, and the mediation of cellular responses to internal and external stimuli are all made possible by these pathways, which include Store-Operated Calcium Entry (SOCE), Mitochondrial Calcium Uniporter (MCU), and Ca²⁺ effectors like CaM. Understanding the processes underlying these pathways is essential for developing successful therapeutic strategies because dysfunction in them can lead to the development of a wide range of pathological illnesses, from cardiovascular ailments to neurodegenerative diseases. Table 1 summarizes the major pathways and effectors in Ca²⁺ signaling that are essential for cellular physiological function.

Table 1 Physiological roles and pathological implications of calcium signaling pathways.

Store-Operated Calcium Entry (SOCE)

A calcium signaling route called SOCE is crucial for preserving intracellular Ca²⁺ homeostasis, particularly in non-excitable cells [40]. The depletion of Ca²⁺ stores in the ER initiates the SOCE mechanism by activating the Ca²⁺ sensor stromal interaction molecule 1 (STIM1) [41]. After detecting a drop in Ca²⁺ concentration, STIM1, which is found on the ER membrane, oligomerizes and moves to the area close to the plasma membrane [42]. Orai1, a specific Ca²⁺ channel in the plasma membrane, is contacted by STIM1 at this site, opening the channel and permitting Ca²⁺ ions from the extracellular environment to enter the cytosol [43]. The influx of Ca²⁺ through the SOCE not only restores ER stores but also produces cytosolic Ca²⁺ signals that control secretion, differentiation, proliferation, and downstream signal transduction [13].

SOCE dysfunction has been associated with various pathological conditions. STIM1 or Orai1 expression mutations or dysregulation can impact muscle and endothelial cell function and result in immunological diseases, including immunodeficiency [44]. Furthermore, SOCE dysregulation has been linked to the development of various cancer types, where increased Ca²⁺ flow through Orai1 promotes tumor cell migration and proliferation, as well as the pathophysiology of cardiovascular diseases, including cardiac hypertrophy and arrhythmias [45]. Mechanistically, Orai1-mediated Ca²⁺ entry activates the Ca²⁺/calmodulin-dependent phosphatase calcineurin, which dephosphorylates NFAT. Dephosphorylated NFAT translocates to the nucleus and induces the expression of pro-migratory and pro-invasive genes (e.g., cyclooxygenase-2 and autotaxin). This axis provides a direct link between enhanced SOCE and tumor cell migration, invasion, and metastatic progression. These results demonstrate that SOCE is a crucial signaling route with therapeutic implications in addition to being a homeostatic mechanism. As a result, SOCE regulation may be a target for clinical intervention in a number of disorders connected to Ca²⁺ [46].

Mitochondrial Calcium Uniporter (MCU)

The transmembrane protein complex known as the Mitochondrial Calcium Uniporter (MCU), which is found on the inner mitochondrial membrane, is essential for maintaining calcium homeostasis within the mitochondria [47]. MCU permits Ca²⁺ ions to enter the mitochondrial matrix, which controls energy generation by activating important tricarboxylic acid cycle (TCA) enzymes and oxidative phosphorylation [48]. Specifically, matrix Ca²⁺ entering via MCU acutely stimulates pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and α-ketoglutarate dehydrogenase (α-KGDH), thereby increasing NADH and FADH₂ supply to the electron-transport chain and coupling Ca²⁺ transients to oxidative phosphorylation and ATP output. MCU regulates mitochondrial Ca²⁺, which supports energy metabolism and is also involved in apoptosis modulation, oxidative stress regulation, and mitochondrial function maintenance [49].

MCU malfunction has been linked to a number of clinical disorders. Reduced myocardial contractility and pathological cardiac remodeling are 2 ways that decreased MCU activity can cause cytosolic Ca²⁺ buildup and compromised cellular energy supply, both of which can lead to heart failure [51]. On the other hand, elevated mitochondrial Ca²⁺ resulting from MCU dysregulation can cause excessive permeability of the mitochondrial membrane, cause neuronal death, and contribute to the development of neurodegenerative illnesses including Parkinson’s and Alzheimer’s [52]. MCU dysregulation is also linked to mitochondrial malfunction and persistent oxidative stress, both of which are risk factors for cardiovascular and metabolic diseases [53].

Calmodulin and Ca²⁺ effectors

The ubiquitous calcium-binding protein CaM is essential for a variety of cellular functions as a modulator of Ca²⁺ signaling [54]. CaM can change its shape when it binds calcium ions because it contains 4 Ca²⁺ binding sites on its EF-hand domain [26]. Then, the active conformation of CaM interacts with several molecular targets, such as kinases, phosphatases, ion channels, and transcription factors, mediating a variety of physiological responses, ranging from the regulation of energy metabolism and synaptic plasticity to muscle contraction, hormone secretion, and cell proliferation [55].

There are important clinical ramifications to CaM’s function as a Ca²⁺ effector. Calcium signaling failure may result from mutations in the CALM gene that impair CaM’s capacity to connect with its targets or bind Ca²⁺ [56]. This condition has been linked to serious heart defects, including congenital arrhythmias, long QT syndrome, and cardiac conduction disorders [57]. According to genetic research, some mutations in CALM might cause aberrant activation or inhibition of downstream Ca²⁺ pathways, which can interfere with regular electrophysiological rhythms and cardiac contractions [58].

Furthermore, calcineurin-NFAT and MAPK are 2 more Ca²⁺-dependent signaling pathways that can be impacted by CaM dysregulation, which can have an effect on organ functions, cell division, and proliferation [59]. As a result, calmodulin serves as a Ca²⁺ sensor as well as a vital connection between intracellular calcium variations and the genetic and functional control of cells [31]. The development of treatment approaches aimed at heart illnesses and diseases linked to calcium signaling dysregulation requires a comprehensive understanding of the function of CaM and related Ca²⁺ effectors.

The role of calcium signaling in normal physiology

Calcium signaling is a central mechanism in the coordination of various physiological processes, in which fluctuations in intracellular Ca²⁺ concentration are translated into specific cellular responses. Calcium ions play an important role in muscle contraction, hormone secretion, regulation of energy metabolism, and nerve signal transmission, including synaptic plasticity and memory formation. Ca²⁺ is a crucial mediator in preserving proper physiological function and overall organismal homeostasis because of its capacity to control molecular and cellular network activities in a temporally and spatially specific manner. Table 2 summarizes the role of Ca²⁺ as a key mediator in various physiological functions, the signaling mechanisms involved, the key molecules or proteins that regulate Ca²⁺ signaling, the main function of each process, and the implications if Ca²⁺ signaling dysfunction occurs.

Table 2 The role of Ca²⁺ signaling in normal physiological processes.

Muscle contraction

Ca²⁺ is essential to the process of muscular contraction in both cardiac and skeletal muscles. Ca²⁺ is released from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR1) in skeletal muscle when the plasma membrane depolarizes due to an action potential [60]. This ion can bind to troponin C due to an increase in cytosolic Ca²⁺ concentration. This causes a conformational shift in the troponin-tropomyosin complex, exposing the actin filament’s active site [61]. This makes it possible to engage with myosin and start the cross-bridge cycle, which causes muscles to contract [62]. The sarcoplasmic/ endoplasmic reticulum Ca²⁺-ATPase (SERCA) pumps Ca²⁺ back into the RS during contraction, enabling muscle relaxation [28].

The phenomenon of calcium-induced calcium release (CICR) is a component of the contraction process in heart muscle [63]. Extracellular Ca²⁺ can enter the cytosol when the cardiac cell membrane depolarizes, opening L-type VGCCs [64]. These Ca²⁺ ions subsequently trigger the ryanodine receptor (RyR2) to release more Ca²⁺ from the sarcoplasmic reticulum [65]. The strength and length of cardiac contraction are determined by these cytosolic Ca²⁺ oscillations, which also control troponin C binding and facilitate myosin-actin contraction [66]. Inadequate control of Ca²⁺ through channels, pumps, or binding proteins can lead to cardiac failure, arrhythmias, or reduced contractility [67].

Hormone secretion

Ca²⁺ is the primary mediator in the method by which endocrine cells secrete hormones through the exocytosis process [68]. Generally speaking, physiological events like hormones, neurotransmitters, or metabolic alterations cause the plasma membrane of endocrine cells to depolarize. This opens VGCCs and permits Ca²⁺ to enter the cytosol from the external environment [69]. This increase in cytosolic Ca²⁺ serves as a signal to activate the exocytosis machinery, including the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate the fusion of secretory vesicles with the plasma membrane [70].

A conformation that permits vesicle-membrane fusion and hormone release into the bloodstream is induced when Ca²⁺ binds to vesicular calcium sensors, like synaptotagmin [71]. This mechanism ensures that hormone secretion occurs rapidly, coordinated, and according to physiological needs, whether it is the release of insulin from pancreatic β cells, the secretion of catecholamines from the adrenal medulla, or peptide hormones from other endocrine cells [72].

Hormone release can be disrupted by Ca²⁺ signaling dysfunction in endocrine cells, and this is linked to a number of clinical diseases [73]. One factor that contributes to the pathophysiology of diabetes mellitus is the dysregulation of Ca²⁺ in pancreatic β cells, which can result in aberrant insulin production [74]. Ca²⁺ disruptions in adrenal medullary cells can also impact catecholamine release and stress reactions [75].

Energy metabolism

Ca²⁺ has a major impact on mitochondrial function, which is the primary way it regulates cellular energy metabolism [76]. Ca²⁺ entering the mitochondrial matrix through the MCU activates a number of important TCA enzymes, including as α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and isocitrate dehydrogenase [77]. Oxidative phosphorylation and ATP synthesis are increased when these enzymes are activated because they produce more NADH and FADH₂, which in turn provide electrons to the electron transport chain [78].

The synthesis of energy is supported by mitochondrial Ca²⁺, which also helps to maintain redox balance and stop oxidative stress from building up [79]. Excess Ca²⁺ can induce the inner mitochondrial membrane’s permeability transition pore (PTP) to open, depolarizing the membrane, reducing ATP synthesis, and initiating the apoptotic process [80]. On the other hand, a lack of mitochondrial Ca²⁺ can impair organ function overall, lower cellular metabolic activity, and limit the body’s ability to adjust to rising energy needs [81].

Neurotransmission and memory

Ca²⁺ controls the release of neurotransmitters at synapses, which is essential for neurotransmission and memory formation [82]. Ca²⁺ can enter the cytosol from the extracellular space when the action potential reaches the presynaptic terminal because the plasma membrane depolarizes, opening VGCCs [83]. Neurotransmitters are exocytosed into the synaptic cleft as a result of this rise in cytosolic Ca²⁺, which causes ion binding to vesicle sensor proteins like synaptotagmin. This fusing of neurotransmitter vesicles with the plasma membrane is mediated by the SNARE complex [84].

Ca²⁺ plays a part in synaptic plasticity processes, including as long-term depression (LTD) and long-term potentiation (LTP), which are the molecular underpinnings of memory formation, in addition to controlling neurotransmitter release [85]. Glutamate receptor sensitivity and synaptic cytoskeleton remodeling are modulated by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which is activated by Ca²⁺ arriving through NMDA receptors on postsynaptic neurons [86]. This pathway’s activation promotes long-term information storage and fortifies synaptic connections.

Dysfunction of Ca²⁺ signaling in the nervous system can lead to impaired neurotransmission, memory, and learning [87]. For instance, excessive or persistent dysregulation of Ca²⁺ can lead to neuronal excitotoxicity by activating proteases and producing free radicals, which is part of the pathophysiology of neurodegenerative illnesses including Parkinson’s and Alzheimer’s [88]. On the other hand, intracellular Ca²⁺ shortage can interfere with the establishment of long-term memory by inhibiting LTP and synaptic plasticity [89]. Figure 2 links these nodes to 4 canonical outputs - excitation-contraction coupling, neurotransmission and plasticity, endocrine secretion, and metabolic coupling - highlighting CICR (LTCC→RyR), synaptotagmin/SNARE-mediated exocytosis, NMDA-CaMKII signaling, and MCU-driven TCA/OXPHOS.

Figure 2 Physiological programs driven by Ca²⁺ signals.

Calcium signaling dysfunction in disease

One of the main contributing factors to the pathophysiology of many chronic diseases has been found to be the dysregulation of Ca²⁺ signaling. Significant physiological abnormalities can result from abnormal Ca²⁺ fluctuations, which can impact a wide range of cellular and tissue activities, including neurons, cardiomyocytes, and endocrine cells. Along with upsetting ionic homeostasis, this disruption sets off the activation of pathogenic signaling pathways that are linked to endocrine dysfunction, diabetes, cardiovascular disease, cancer, and neurodegeneration. The development of more targeted diagnostic and treatment approaches requires a comprehensive understanding of the mechanisms underlying Ca²⁺ dysregulation in the setting of disease. Table 3 presents a summary of the mechanisms of Ca²⁺ signaling dysfunction in various types of diseases, the molecules and pathways involved, the physiological impact or pathological consequences that arise, and potential therapeutic targets.

Table 3 Ca²⁺ signaling dysfunction and its role in the pathogenesis of various diseases.

Neurodegeneration

Ca²⁺ signaling dysfunction is a central mechanism in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s and Parkinson’s [9]. Excessive cytosolic Ca²⁺ buildup is the outcome of Ca²⁺ dysregulation in Alzheimer’s disease, which is caused by disruption of ion channels, Ca²⁺ pumps, and glutamate receptors [90]. This rise in Ca²⁺ damages the cytoskeleton, cell membranes, and organelles, including mitochondria, by causing the activation of proteases, phospholipases, and free radicals [91]. Additionally, aberrant tau protein phosphorylation and β-amyloid plaque development are brought on by chronic Ca²⁺ buildup, which leads to neuronal degeneration and compromised synaptic function [92].

Dopaminergic neurons in the substantia nigra pars compacta are extremely susceptible to Ca²⁺ stress in Parkinson’s disease [93]. L-type Ca²⁺ channel dysfunction and mitochondrial homeostasis dysregulation raise intracellular Ca²⁺ load, which sets off oxidative stress, depolarization of the mitochondrial membrane, and apoptotic pathway activation [94]. Both the motor and non-motor symptoms that are typical of Parkinson’s disease are caused by the unchecked buildup of Ca²⁺, which damages synapses and kills dopaminergic neurons [95].

Cardiovascular disease

Ca²⁺ signaling dysfunction is a major factor in the pathogenesis of various cardiovascular diseases, including cardiac hypertrophy, heart failure, and arrhythmias [96]. Through the sarcoplasmic reticulum’s CICR mechanism, which binds to troponin C and ion return to the reticulum via SERCA, cytosolic Ca²⁺ variations in a healthy myocardium control cardiac contraction and relaxation [97]. Chronic increases in cytosolic Ca²⁺ or defective Ca²⁺ emptying result from dysfunction in this control, which can be caused by mutations in Ca²⁺ regulatory proteins or by dysregulation of the SOCE and MCU pathways. These conditions cause asynchronous contractions and cellular hypertrophy [98].

Excessive cytosolic Ca²⁺ buildup in heart failure reduces cardiac contractility and raises mitochondrial oxidative stress, which lowers ATP synthesis and initiates the apoptotic pathway [99]. Additionally, aberrant depolarization and spontaneous release of Ca²⁺ from the sarcoplasmic reticulum are 2 ways whereby Ca²⁺ dysregulation in cardiac conduction cells and Purkinje tissue leads to arrhythmias, such as atrial and ventricular fibrillation [100].

Pathological cardiac remodeling is also influenced by disruption in Ca²⁺ signaling [50]. Hemodynamic load-induced cardiac hypertrophy raises Ca²⁺ channel expression and activity, intensifying maladaptive growth signals and raising the risk of chronic heart failure [101]. Therefore, pharmaceutical interventions that aim to improve contractility, prevent arrhythmias, and restrict cardiac remodeling should focus on modulating the Ca²⁺ signaling pathway, which includes the activity of SERCA, RyR, and L-type channels [102].

Cancer

The pathogenesis and progression of cancer are significantly influenced by Ca²⁺ signaling dysregulation, which controls the proliferation, migration, invasion, and death of tumor cells [103]. Dysregulation of plasma Ca²⁺ channels and organelles, such as VGCCs, SOCE via STIM1/Orai1, and MCU, can lead to abnormal intracellular Ca²⁺ fluctuations [104]. Overactivity of these pathways causes pro-proliferative and anti-apoptotic genes to be expressed, activates Ca²⁺-dependent kinases and phosphatases, and raises cytosolic Ca²⁺ [36].

Upregulation of SOCE via STIM1/Orai1 has been linked to aggressive cell migration, tissue invasion, and metastasis in a number of cancer types, including colorectal, lung, and breast malignancies [105]. Furthermore, MCU-mediated dysregulation of mitochondrial Ca²⁺ influences ATP synthesis, redox balance, and apoptosis resistance, all of which promote tumor cell survival in oxidatively challenged conditions [106]. Dysfunction of Ca²⁺ signaling also interacts with other oncogenic pathways, including MAPK and PI3K/AKT, which increase the capacity of cancer cells to proliferate and adapt metabolically [107].

There is a lot of therapeutic potential in targeting Ca²⁺ signaling in cancer cells, whether via SOCE suppression, MCU regulation, or blocking particular Ca²⁺ channels [108]. These treatments can prevent metastasis, improve sensitivity to chemotherapy, and decrease tumor growth [109]. Therefore, a better comprehension of Ca²⁺ dysregulation in cancer creates prospects for the creation of more targeted and efficient molecular mechanism-based treatments.

Diabetes and endocrine disorders

Ca²⁺ signaling dysfunction plays a critical role in the pathogenesis of metabolic and endocrine disorders, including diabetes mellitus and pancreatic hormone dysfunction. Proper cytosolic Ca²⁺ fluctuations are necessary for insulin production in response to glucose in pancreatic β cells [110]. Increased glucose causes the cell membrane to depolarize, opening VGCCs that let Ca²⁺ in and cause insulin vesicle fusion through SNARE proteins [111]. Insulin secretion is inhibited and hyperglycemia is exacerbated by Ca²⁺ dysregulation, which manifests as either reduced Ca²⁺ flow or compromised cytosolic equilibrium [112].

Systemic metabolic balance may also be upset by Ca²⁺ dysregulation, which also influences the release of other hormones such as glucagon, catecholamines, and thyroid hormones [113]. Cell dysfunction may worsen as a result of oxidative stress, reduced ATP synthesis, and apoptosis pathway activation brought on by excessive mitochondrial Ca²⁺ buildup or diminished MCU activity in endocrine cells [114]. This disorder raises the risk of cardiometabolic problems in addition to affecting glucose homeostasis [115]. Figure 3 maps disease-relevant perturbations (↑/↓ SOCE; RyR leak; SERCA downregulation; VGCC variants; MCU↑/NCLX↓; CaM/CaMK/calcineurin mis-signaling) onto neurodegeneration, cardiac remodeling/arrhythmia, cancer, and endocrine dysfunction, with directionality indicated.

Figure 3 Pathological perturbations of Ca²⁺ signaling across diseases.

Therapeutic approaches and interventions

Therapeutic strategies that target Ca²⁺ signaling have promising prospects for the treatment of numerous illnesses linked to this ion’s dysfunction. Intervention tactics include direct Ca²⁺ channel manipulation, controlling certain molecular targets like STIM1, Orai1, and MCU, and using epigenetic techniques to take advantage of Ca²⁺’s impact on gene expression. In addition to restoring calcium homeostasis, these strategies seek to enhance tissue and cellular capabilities compromised by Ca²⁺ signaling dysregulation, laying the groundwork for the creation of more targeted and potent novel treatments.

Modulation of Ca²⁺ channels

Ca²⁺ channel modulation is a key therapeutic approach for the treatment of a number of cardiovascular conditions, including as hypertension and arrhythmias [116]. Myocardial contraction and vascular tone are significantly influenced by L-type Ca²⁺ channels found in cardiac muscle cells and vascular smooth muscle cells [117]. Increased smooth muscle and cardiac contractions due to excessive activation or dysregulation of these channels might raise blood pressure and increase the risk of arrhythmias [118].

The use of Ca²⁺ channel antagonists calcium channel blockers (CCBs) aims to inhibit the entry of Ca²⁺ into cells through L-type channels, thereby reducing heart muscle contractility, widening blood vessels, and stabilizing heart rhythm [119]. These medications have been demonstrated to be successful in lowering blood pressure in patients with hypertension, lessening the heart’s stress, and shielding individuals with arrhythmias from tachycardia and atrial fibrillation episodes [120]. Furthermore, kinase activity and Ca²⁺-dependent gene expression are 2 downstream signaling pathways that are impacted by Ca²⁺ channel regulation, which offers further protection against oxidative stress and abnormal cardiac remodeling [14].

Molecular target of Ca²⁺

More specialized approaches to treating a variety of disorders linked to Ca²⁺ dysregulation are provided by therapeutic approaches that target important molecules in calcium signaling, such as STIM1, Orai1, and MCU. The SOCE pathway, which mediates the inflow of Ca²⁺ from the external environment when endoplasmic reticulum reserves are exhausted, is largely mediated by STIM1 and Orai1 [121]. This pathway’s overactivation has been connected to immunological diseases, cancer, and heart hypertrophy [122]. Therapeutic potential in oncology and cardiovascular disease can be achieved by selectively inhibiting STIM1 or Orai1, which can stabilize cytosolic Ca²⁺ fluctuations, decrease the activation of maladaptive cell growth pathways, and prevent tumor cell migration and proliferation [123].

In the meantime, MCU is involved in the control of mitochondrial Ca²⁺, which is necessary for the synthesis of ATP, the control of oxidative stress, and apoptosis [124]. Excessive mitochondrial Ca²⁺ accumulation or reduced Ca²⁺ uptake due to MCU dysfunction can result in cardiac failure, brain injury, and metabolic problems [125]. Through the use of inhibitors or selective agonists, MCU can be modified to directly regulate mitochondrial Ca²⁺ homeostasis, thereby restoring cellular energy capacity and lowering oxidative stress [126].

This molecular target-based method demonstrates that STIM1, Orai1, and MCU treatments influence downstream signaling cascades that are critical for cell proliferation, differentiation, contractility, and survival in addition to directly modulating Ca²⁺ fluctuations [127]. This approach lays the groundwork for the creation of safer and more efficient precision treatments for diseases linked to calcium signaling dysregulation, including metabolic, neurodegenerative, cardiovascular, and oncological conditions.

Epigenetic strategies

Through epigenetic pathways, Ca²⁺ affects the regulation of gene expression in addition to its involvement in cytosolic and mitochondrial signaling [128]. Variations in cytosolic Ca²⁺ can activate a number of transcription factors, such as NFAT, CREB, and myocyte enhancer factor 2 (MEF2), which directly control the expression of genes related to cell survival, proliferation, differentiation, and contractility [129]. This pathway, which connects Ca²⁺ fluctuations to chromatin changes and transcriptional activity, is frequently activated by contact with Ca²⁺/calmodulin-dependent protein kinases (CaMKs) or phosphatases like calcineurin [130].

Ca²⁺ signaling is used in epigenetic-based treatment techniques that seek to precisely alter gene expression, for instance, by decreasing the production of pro-apoptotic genes or enhancing the activation of protective transcription pathways [131]. This approach may be used in cancer, neurological illnesses, and cardiovascular conditions where the course of the disease is aided by the deregulation of gene expression brought on by Ca²⁺ fluctuations [132]. For instance, CaMK/CREB regulation can support synaptic plasticity and memory function in neurodegenerative illnesses, while NFAT activation via Ca²⁺ can enhance cardiomyocyte cell regeneration following injury [133]. Figure 4 summarizes the therapeutic landscape from membrane to nucleus - VGCC and SOCE modulators, RyR stabilizers, SERCA activators, MCU/NCLX targeting, and downstream inhibitors of calcineurin, CaMK, and MAPK - aligned to indications and biomarker readouts.

Figure 4 Therapeutic targeting map of Ca²⁺ pathways.

Future research directions

Ca²⁺ signaling has been identified as a central mechanism regulating a wide range of physiological processes, from muscle contraction and hormone secretion to neurotransmission and energy metabolism [13]. Furthermore, dysregulation of Ca²⁺ plays a major role in the pathophysiology of a number of illnesses, such as cancer, diabetes, cardiovascular disease, and neurodegeneration [5-8]. These results highlight how crucial it is to fully comprehend Ca²⁺ dynamics in cellular and tissue settings, both in healthy and diseased settings.

Understanding the intricate relationships between Ca²⁺ signaling pathways, transcription factors, epigenetic modification, and downstream effects on different cell types is still difficult, despite the fact that prior research has shown important functions for molecules including STIM1, Orai1, MCU, and calmodulin [134]. These restrictions create the possibility of conducting more thorough studies on the coordination of Ca²⁺ variations in space and time, as well as their effects on the overall physiology of organs and systems.

Future studies should concentrate on developing novel technologies and experimental methodologies, such as cellular proteomic and transcriptome analysis, in vivo Ca²⁺ imaging, and molecular and epigenetic target-based treatment approaches [14]. These investigations could help create novel treatments that restore Ca²⁺ homeostasis, uncover possible illness biomarkers, and offer more accurate insights into Ca²⁺ signaling pathways. Therefore, it is anticipated that additional study in this field will not only deepen our grasp of the scientific foundation but also open the door to more potent clinical treatments for disorders linked to calcium dysregulation.

Conslusions

This review synthesizes calcium signaling across cellular compartments to provide a systems-level account of how calcium regulates physiology and contributes to disease. The evidence indicates that pathogenesis more often reflects imbalance within an integrated network comprising store-operated calcium entry (SOCE), mitochondrial calcium uniporter (MCU)-mediated flux, and calmodulin (CaM)-driven transcriptional programs than defects in any single molecule. This network links plasma-membrane influx with calcium handling by the endoplasmic and sarcoplasmic reticulum, mitochondrial control of bioenergetics, and gene regulation in the nucleus.

Therapeutically, restoring network-level calcium balance is likely to be more effective than single-target blockade. Promising avenues include context-specific modulation of SOCE components such as STIM1 and Orai1, regulators of reticular calcium cycling such as SERCA and ryanodine receptors, mitochondrial transport via MCU and NCLX, and downstream calmodulin-dependent pathways including calcineurin-NFAT and CaMK-CREB. Future work should combine quantitative calcium imaging, multi-omics profiling of network nodes, and causal perturbation in human-relevant models to define biomarkers, stratify patients, and guide rational multi-node interventions. Viewed through this integrated lens, calcium signaling remains both a central regulator of normal physiology and a tractable target for next-generation therapies across neurodegenerative, cardiovascular, metabolic, and oncologic diseases.

Acknowledgements

The authors would like to express their sincere gratitude to the National Research and Innovation Agency (BRIN) and the Indonesia Endowment Fund for Education (LPDP) for financial support through the Research and Innovation for Advanced Indonesia (RIIM) Program – Competitive Wave 7, as stipulated in the Decree of the Deputy for Research and Innovation Facilitation of BRIN No. 61/II.7/HK/2024. The authors also acknowledge material and immaterial support from the Research Organization for Agriculture and Food (ORPP BRIN) and the valuable assistance of the Research Center for Mineral Technology, BRIN, in the preparation and completion of this manuscript. Collaborative contributions from Institut Teknologi Sumatera (ITERA) are gratefully appreciated.

Declaration of Generative AI in Scientific Writing

The authors declare that no generative AI tools were used in the writing or preparation of this manuscript.

CRediT Author Statement

Aswin Rafif Khairullah: Conceptualization, Literature review, and Writing – original draft. Dea Anita Ariani Kurniasih: Literature review, Data curation, and Writing – original draft. Ilma Fauziah Ma’ruf: Literature review, Data curation, and Writing – original draft. Bima Putra Pratama: Reference management, Data curation, and Validation. Mohammad Sukmanadi: Conceptualization, Supervision, Funding acquisition, and Writing – review and editing. Arif Nur Muhammad Ansori: Writing – review and editing, Validation, and Supervision. Imam Mustofa: Manuscript preparation, Critical review, and Validation. Bantari Wisynu Kusuma Wardhani: Manuscript preparation, Critical review, and Validation. Riza Zainuddin Ahmad: Methodological review, Critical revision, and Validation. Eny Martindah: Writing – review and editing, Supervision, and Validation. Sri Mulyati: Reference management, Resources, and Validation. Wita Yulianti: Manuscript preparation, Critical review, and Validation. Abdul Hadi Furqoni: Reference management, Resources, and Validation. Saifur Rehman: Project administration, Supervision, Writing – review and editing, and Validation. Syahputra Wibowo: Writing – review and editing, Visualization, and Validation. Fadhila Utari: Manuscript preparation, Critical review, and Validation.

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