Search Results (177)

Effective rhizobium–legume symbiosis depends on multiple molecular signaling pathways, integrating not only classical nodulation factors and surface polysaccharides but also diverse protein secretion systems. Among them, the Type VI Secretion System (T6SS) has emerged as a key player, due to its dual roles in interbacterial competition and interactions with eukaryotic hosts, though its contribution to symbiosis remains unclear. Key regulatory messengers, including the main autoinducer of the quorum sensing (QS) systems, the N-acyl homoserine lactones (AHLs), and the second messenger cyclic di-GMP (c-di-GMP), modulate the transition between motility and biofilm formation, especially in the context of bacteria interacting with eukaryotes, including rhizobia. While c-di-GMP’s impact on exopolysaccharide production in these organisms is well established, its influence on protein secretion systems, particularly in conjunction with QS, is largely unexplored. To contribute to the study of such interplay, we artificially increased intracellular c-di-GMP levels by overexpressing a heterologous diguanylate cyclase in three Sinorhizobium fredii strains of agronomic relevance. This engineering revealed strain-specific outcomes, since elevated c-di-GMP enhanced biofilm development in two strains, but reduced it in another. Furthermore, using β-galactosidase expression assays, we confirmed that both high c-di-GMP and/or AHL concentrations contribute to the transcriptional activation of T6SS. These results demonstrate a direct regulatory link between c-di-GMP, QS signals, and T6SS expression, shedding light on the multilayered control mechanisms that structure beneficial rhizobia–plant interactions. Full article

UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the Trans Golgi area. LacCer is a bioactive lipid second messenger that activates an “oxidative stress pathway”, leading to critical phenotypes, e.g., cell proliferation, migration angiogenesis, autophagy, and apoptosis. It also activates an “inflammatory pathway” that contributes to the progression of disease pathology. β-1,4-GalT-V gene expression is regulated by the binding of the transcription factor Sp-1, one of the most O-GlcNAcylated nuclear factors. This review elaborates the role of the Sp-1/GalT-V axis in disease phenotypes and therapeutic approaches targeting not only Sp-1 but also Notch-1, Wnt-1 frizzled, hedgehog, and β-catenin. Recent evidence suggests that β-1,4GalT-V may glycosylate Notch-1 and, thus, regulate a VEGF-independent angiogenic pathway, promoting glioma-like stem cell differentiation into endothelial cells, thus contributing to angiogenesis. These findings have significant implications for cancer and cardiovascular disease, as tumor vascularization often resumes aggressively following anti-VEGF therapy. Moreover, LacCer can induce angiogenesis independent of VEGF and its level are reported to be high in tumor tissues. Thus, targeting both VEGF-dependent and VEGF-independent pathways may offer novel therapeutic strategies. This review also presents an up-to-date therapeutic approach targeting the β-1,4-GalT-V interactome. In summary, the β-1,4-GalT-V interactome orchestrates a broad network of signaling pathways essential for maintaining cellular homeostasis. Conversely, its dysregulation can promote unchecked proliferation, angiogenesis, and inflammation, contributing to the initiation and progression of multiple diseases. Environmental factors and smoking can influence β-1,4-GalT-V expression and its interactome, whereas elevated β-1,4-GalT-V expression may serve as a diagnostic biomarker of colorectal cancer, inflammation—exacerbated by factors that may worsen pre-existing cancer malignancies, such as smoking and a Western diet—and atherosclerosis, amplifying disease progression. Increased β-1,4-GalT-V expression is frequently associated with tumor aggressiveness and chronic inflammation, underscoring its potential as both a biomarker and therapeutic target in colorectal and other β-1,4-GalT-V-driven cancers, as well as in cardiovascular and inflammatory diseases. Full article

Background. The STING protein is activated by the second messenger cGAMP to promote the innate immune response against infections. Beyond this role, a chronically overactive STING signaling has been described in several disorders. Patients with severe COVID-19 exhibit a hyper-inflammatory response (the cytokine storm) that is in part mediated by the cGAS-STING pathway. Several STING inhibitors may protect from severe COVID-19 by down-regulating several inflammatory cytokines. This pathway has been implicated in the establishment of an optimal antiviral vaccine response. STING agonists as adjuvants improved the IgG titers against the SARS-CoV-2 Spike protein vaccines. Methods. We investigated the association between two common functional STING1/TMEM173 polymorphisms (rs78233829 C>G/p.Gly230Ala and rs1131769C>T/p.His232Arg) and severe COVID-19 requiring hospitalization. A total of 801 non-vaccinated and 105 fully vaccinated (mRNA vaccine) patients, as well as 300 population controls, were genotyped. Frequencies between the groups were statistically compared. Results. There were no differences for the STING1 variant frequencies between non-vaccinated patients and controls. Vaccinated patients showed a significantly higher frequency of rs78233829 C (230Gly) compared to non-vaccinated patients (CC vs. CG + GG; p = 0.003; OR = 2.13; 1.29–3.50). The two STING1 variants were in strong linkage disequilibrium, with the rs78233829 C haplotypes being significantly more common in the vaccinated (p = 0.02; OR = 1.66; 95%CI = 1.01–2.55). We also studied the LTZFL1 rs67959919 G/A polymorphism that was significantly associated with severe COVID-19 (p < 0.001; OR = 1.83; 95%CI = 1.28–2.63). However, there were no differences between the non-vaccinated and vaccinated patients for this polymorphism. Conclusions. We report a significant association between common functional STING1 polymorphisms and the risk of developing severe COVID-19 among fully vaccinated patients. Full article

Listeria monocytogenes is a foodborne pathogen frequently exposed to oxidative stress in diverse environmental conditions. Cyclic di-AMP (c-di-AMP) is a second messenger that plays a key role in stress resistance. This study investigates the role of pdeA (degrades c-di-AMP) and how c-di-AMP accumulation affects catalase activity and oxidative stress response and gene expression. Survival and catalase activity assays were conducted under oxidative stress, and c-di-AMP levels were quantified in L. monocytogenes 10403S under aerobic, anaerobic, and L-cysteine-supplemented conditions. ΔpdeA, which accumulates c-di-AMP, exhibited greater sensitivity to oxidative stress (4.6 log reduction for the wild type (WT) vs 7.34 log reduction for ΔpdeA at 10 h) and lower catalase activity than the WT in the early stationary phase. However, in the late stationary phase, while the catalase activity levels of ΔpdeA remained stable (~6.33 cm foam height), it became resistant to oxidative stress (5.85 log reduction). These findings indicate that pdeA contributes to catalase activity in L. monocytogenes. Transcriptomic analysis revealed differential expression of pathways mainly including pentose phosphate pathway, carbon metabolism, O-antigen nucleotide sugar biosynthesis and ABC transporters in ΔpdeA compared to WT. Our transcriptomic data provided promising insights into the molecular mechanisms underlying c-di-AMP regulation, which may enhance stress resistance. Moreover, oxidative stress led to increased intracellular c-di-AMP levels. Under L-cysteine supplementation, catalase activity levels in WT were similar to ΔpdeA (~1.86 cm foam height for both), but the latter showed enhanced oxidative stress resistance and c-di-AMP levels. Anaerobic conditions also elevated c-di-AMP levels in WT and ΔpdeA but resulted in greater oxidative stress sensitivity. Understanding these regulatory mechanisms provides valuable insights into oxidative stress resistance, with potential implications for food safety and pathogen control. Full article

Receptor-mediated endocytosis (RME) is a commonly recognized receptor internalization process of receptor degradation or recycling. However, recent studies have supported that RME is closely related to signal propagation and amplification from the plasma membrane to the cytosol. Few studies have elucidated the role of H₂O₂, a mild oxidant among reactive oxygen species (ROS) in RME and second messenger of signal propagation. In the present study, we investigated the regulatory function of H₂O₂ in early endosomes during signaling throughout receptor-mediated endocytosis. In mammalian cells with a physiological amount of H₂O₂ generated during epidermal growth factor (EGF) activation, fluorescence imaging showed that the levels of two activating phosphorylations on Ser⁴⁷³ and Thr³⁰⁸ of Akt were transiently increased in the plasma membrane, but the predominant p-Akt on Ser⁴⁷³ appeared in early endosomes. To examine the role of endosomal H₂O₂ molecules as signaling mediators of Akt activation in endosomes, we modulated endosomal H₂O₂ through the ectopic expression of an endosomal-targeting catalase (Cat-Endo). The forced removal of endosomal H₂O₂ inhibited the Akt phosphorylation on Ser⁴⁷³ but not on Thr³⁰⁸. The levels of mSIN and rictor, two components of mTORC2 that work as a kinase in Akt phosphorylation on Ser⁴⁷³, were also selectively diminished in the early endosomes of Cat-Endo-expressing cells. We also observed a decrease in the endosomal level of the adaptor protein containing the PH domain, the PTB domain, and the Leucine zipper motif 1 (APPL1) protein, which is an effector of Rab5 and key player in the assembly of signaling complexes regulating the Akt pathway in Cat-Endo-expressing cells compared with those in normal cells. Therefore, the H₂O₂-dependent recruitment of the APPL1 adaptor protein into endosomes was required for full Akt activation. We proposed that endosomal H₂O₂ is a promoter of Akt signaling. Full article

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K⁺ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K⁺ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K⁺ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K⁺ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K⁺ channel blockers), and apamin and charybdotoxin (Ca²⁺-activated K⁺ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K⁺ channel pathway. Full article

Dictyostelium is a unique model used to study the complex and interactive cyclic nucleotide signaling pathways that regulate multicellular development. Dictyostelium grow as individual single cells, but in the absence of nutrients, they initiate a multicellular developmental program. Central to this is secreted cAMP, a primary GPCR-response signal. Activated cAMP receptors at the cell surface direct a number of downstream signaling pathways, including synthesis of the intracellular second messengers cAMP and cGMP. These, in turn, activate a series of downstream targets that direct chemotaxis within extracellular cAMP gradients, multicellular aggregation, and, ultimately, cell-specific gene expression, morphogenesis, and cytodifferentiation. Extracellular cAMP and intracellular cAMP and cGMP exhibit rapid fluctuations in concentrations and are, thus, subject to exquisite regulation by both synthesis and degradation. The Dictyostelium genome encodes seven phosphodiesterases (PDEs) that degrade cyclic nucleotides to nucleotide 5’-monophosphates. Each PDE has a distinct structure, substrate specificity, regulatory input, cellular localization, and developmentally regulated expression pattern. The intra- or extra-cellular localizations and enzymatic specificities for cAMP or cGMP are essential for degradative precision at different developmental stages. We discuss the diverse PDEs, the nucleotide cyclases, and the target proteins for cAMP and cGMP in Dictyostelium. We further outline the major molecular, cellular, and developmental events regulated by cyclic nucleotide signaling, with emphasis on the input of each PDE and consequence of loss-of-function mutations. Finally, we relate the structures and functions of the Dictyostelium PDEs with those of humans and in the context of potential therapeutic understandings. Full article

Objectives: This study aimed to elucidate the effects of messenger RNA (mRNA) and inactivated coronavirus disease 2019 (COVID-19) vaccines on ovarian histology and reserve in rats. Methods: Thirty female Wistar albino rats, aged 16–24 weeks, were randomly divided into three groups (n = 10): control, mRNA vaccine, and inactivated vaccine groups. Each vaccine group received two doses (on day 0 and day 28) at human-equivalent doses. Four weeks post-second vaccination, ovarian tissues were harvested for analysis. Results: Immunohistochemical analysis was performed to evaluate the expression of transforming growth factor beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), caspase-3, and anti-Müllerian hormone (AMH) in ovarian follicles. Both vaccines induced significant increases in TGF-β1, VEGF, and caspase-3 expression, with more pronounced effects in the mRNA vaccine group. Conversely, AMH expression in the granulosa cells of primary, secondary, and antral follicles showed marked reductions (p < 0.001). The counts of primordial, primary, and secondary follicles decreased significantly in the inactivated vaccine group relative to controls and further in the mRNA vaccine group compared to the inactivated group (p < 0.001). Additionally, the mRNA vaccine group exhibited a decrease in antral and preovulatory follicles and an increase in atretic follicles compared to the other groups (p < 0.05). The serum AMH level was diminished with the mRNA vaccination in comparison with the control and inactivated groups. Conclusions: Our findings suggest that both mRNA and inactivated COVID-19 vaccines may detrimentally impact ovarian reserve in rats, primarily through accelerated follicular loss and alterations in apoptotic pathways during folliculogenesis. Given these observations in a rat model, further investigations into the vaccines’ effects on human ovarian reserve are needed. Full article

Arbuscular mycorrhizal (AM) symbiosis, a mutually beneficial interaction between plant roots and AM fungi, plays a key role in plant growth, nutrient acquisition, and stress tolerance, which make it a major focus for sustainable agricultural strategies. This intricate association involves extensive transcriptional reprogramming in host plant cells during the formation of arbuscules, which are specialized fungal structures for nutrient exchange. The symbiosis is initiated by molecular signaling pathways triggered by fungal chitooligosaccharides and strigolactones released by plant roots, which act as chemoattractants and signaling molecules to promote fungal spore germination, colonization, and arbuscule development. Calcium spiking, mediated by LysM domain receptor kinases, serves as a critical second messenger in coordinating fungal infection and intracellular accommodation. GRAS transcription factors are key components that regulate the transcriptional networks necessary for arbuscule development and maintenance, while small RNAs (sRNAs) from both plant and fungi, contribute to modifications in gene expression, including potential bidirectional sRNA exchange to modulate symbiosis. Understanding the molecular mechanisms related to AM symbiosis may provide valuable insights for implementation of strategies related to enhancing plant productivity and resilience. Full article

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer’s, Parkinson’s, and Huntington’s diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions. Full article

Pulsed Electromagnetic Fields (PEMF) are widely used, with excellent clinical outcomes. However, their mechanism of action has not yet been completely understood. The purpose of this review is to describe current observations on the mechanisms of PEMF, together with its clinical efficacy. Osteoblast responsiveness to PEMF is described on several scales, from the cell membrane to clinically relevant bone formation. PEMF has been shown to activate membrane adenosine receptors. The role of adenosine receptors in activating intracellular second messenger pathways, such as the canonical Wnt/β-catenin pathway and the mitogen-activated protein kinases (MAPK) pathway, is described. The responsiveness of osteoblasts and the synthesis of structural and signaling proteins constitute the role of PEMFs in promoting osteogenesis and bone matrix synthesis, and they are described. Multiple studies, ranging from observational and randomized to meta-analyses that investigate the clinical efficacy of PEMF, are described. This review presents a favorable conclusion on the clinical effects of PEMF while unlocking the “black box” of PEMF’s mechanism of action, thus improving confidence in the clinical utility of PEMF in bone repair. Full article

Phyllostachys edulis, an economically and ecologically significant bamboo species, has substantial research value in applications as a bamboo substitute for plastic and in forest carbon sequestration. However, frequent seasonal low-temperature events due to global climate change affect the growth, development, and productivity of P. edulis. Calcium signaling, serving as a versatile second messenger, is involved in various stress responses and nitrogen metabolism. In this study, we analyzed the calcium signaling dynamics and regulatory strategies in P. edulis under chilling stress. Differentially expressed genes (DEGs) from the CBF families, AMT families, NRT families, and Ca²⁺ sensor families, including CaM, CDPK, and CBL, were identified using transcriptomics. Additionally, we explored the law of Ca²⁺ flux and distribution in the roots of P. edulis under chilling stress and validated these findings by assessing the content or activity of Ca²⁺ sensor proteins and nitrogen transport proteins in the roots. The results indicated that the Ca²⁺ sensor families of CaM, CDPK, and CBL in P. edulis exhibited significant transcriptional changes under chilling stress. Notably, PH02Gene03957, PH02Gene42787, and PH02Gene19300 were significantly upregulated, while the expressions of PH02Gene08456, PH02Gene01209, and PH02Gene37879 were suppressed. In particular, the expression levels of the CBF family gene PH02Gene14168, a downstream target gene of the calcium channels, increased significantly. P. edulis exhibited an influx of Ca²⁺ at the root, accompanied by oscillating negative peaks under chilling stress. Spatially, the cytosolic calcium concentration ([Ca²⁺]_cyt) within the root cells increased. The CIPK family genes, interacting with Ca²⁺-CBL in downstream signaling pathways, showed significant differential expressions. In addition, the expressions of the NRT and AMT family genes changed correspondingly. Our study demonstrates that Ca²⁺ signaling is involved in the regulatory network of P. edulis under chilling stress. [Ca²⁺]_cyt fluctuations in the roots of P. edulis are induced by chilling stress, reflecting an influx of extracellular Ca²⁺. Upon binding to Ca²⁺, downstream target genes from the CBF family are activated. Within the Ca²⁺–CBL–CIPK signaling network, the CIPK family plays a crucial role in nitrogen metabolism pathways. Full article

The calcium cation is a crucial signaling molecule involved in numerous cellular pathways. Beyond its role as a messenger or modulator in intracellular cascades, calcium’s function in excitable cells, including nerve impulse transmission, is remarkable. The central role of calcium in nervous activity has driven the rapid development of fluorescent techniques for monitoring this cation in living cells. Specifically, genetically encoded calcium indicators (GECIs) are the most in-demand molecular tools in their class. In this work, we address two issues of calcium imaging by designing indicators based on the successful GCaMP6 backbone and the fluorescent protein BrUSLEE. The first indicator variant (GCaMP6s-BrUS), with a reduced, calcium-insensitive fluorescence lifetime, has potential in monitoring calcium dynamics with a high temporal resolution in combination with advanced microscopy techniques, such as light beads microscopy, where the fluorescence lifetime limits acquisition speed. Conversely, the second variant (GCaMP6s-BrUS-145), with a flexible, calcium-sensitive fluorescence lifetime, is relevant for static measurements, particularly for determining absolute calcium concentration values using fluorescence lifetime imaging microscopy (FLIM). To identify the structural determinants of calcium sensitivity in these indicator variants, we determine their spatial structures. A comparative structural analysis allowed the optimization of the GCaMP6s-BrUS construct, resulting in an indicator variant combining calcium-sensitive behavior in the time domain and enhanced molecular brightness. Our data may serve as a starting point for further engineering efforts towards improved GECI variants with fine-tuned fluorescence lifetimes. Full article

Purpose of Review: This review aims to describe the role of limbic system-associated membrane protein (LSAMP) in normal- and pathophysiology, and its potential implications in oncogenesis. We have summarized research articles reporting the role of LSAMP in the development of a variety of malignancies, such as clear cell renal cell carcinoma, prostatic adenocarcinoma, lung adenocarcinoma, osteosarcoma, neuroblastoma, acute myeloid leukemia, and epithelial ovarian cancer. We also examine the current understanding of how defects in LSAMP gene function may contribute to oncogenesis. Finally, this review discusses the implications of future LSAMP research and clinical applications. Recent Findings: LSAMP has been originally described as a surface adhesion glycoprotein expressed on cortical and subcortical neuronal somas and dendrites during the development of the limbic system. It is categorized as part of the IgLON immunoglobulin superfamily of cell-adhesion molecules and is involved in regulating neurite outgrowth and neural synapse generation. LSAMP is both aberrantly expressed and implicated in the development of neuropsychiatric disorders due to its role in the formation of specific neuronal connections within the brain. Additionally, LSAMP has been shown to support brain plasticity via the formation of neuronal synapses and is involved in modulating the hypothalamus in anxiogenic environments. In murine studies, the loss of LSAMP expression was associated with decreased sensitivity to amphetamine, increased sensitivity to benzodiazepines, increased hyperactivity in new environments, abnormal social behavior, decreased aggressive behavior, and decreased anxiety. Findings have suggested that LSAMP plays a role in attuning serotonergic activity as well as GABA activity. Given its importance to limbic system development, LSAMP has also been studied in the context of suicide. In malignancies, LSAMP may play a significant role as a putative tumor suppressor, the loss of which leads to more aggressive phenotypes and mortality from metastatic disease. Loss of the LSAMP gene facilitates epithelial-mesenchymal transition, or EMT, where epithelial cells lose adhesion and gain the motile properties associated with mesenchymal cells. Additionally, LSAMP and the function of the RTK pathway have been implicated in tumorigenesis through the modulation of RTK expression in cell membranes and the activation of second messenger pathways and β-catenin. Summary: Beyond its many roles in the limbic system, LSAMP functions as a putative tumor suppressor protein. Loss of the LSAMP gene is thought to facilitate epithelial-mesenchymal transition, or EMT, where cells lose adhesion and migrate to distant organs. LSAMP’s role in modulating RTK activity and downstream ERK and Akt pathways adds to a large body of data investigating RTK expression in oncogenesis. The characteristics of LSAMP defects and their association with aggressive and metastatic disease are evident in reports on clear cell renal cell carcinoma, prostatic adenocarcinoma, lung adenocarcinoma, osteosarcoma, neuroblastoma, acute myeloid leukemia, and epithelial ovarian cancer. Full article

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca²⁺_i) homeostasis. The release of Ca²⁺ from IP₃Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP₃Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP₃Rs results in the dysregulation of Ca²⁺ concentration ([Ca²⁺]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP₃Rs, i.e., IP₃R1 and IP₃R2, have been identified. Notably, IP₃R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP₃R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP₃Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP₃R antagonists have emerged as promising strategies against IP₃R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP₃Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases. Full article