Purinergic signalling review

Ligand-gated ion channels are a large category of essential ion channels, whose superfamily members may modulate their state by binding to specific ligands, allowing specific ions to pass through the cell membrane. Purinergic ligand- gated ion channel(P2X)and ASIC (acid-sensitive ion channel) are representative members of trimeric ligand-gated ion channels. Recent studies have shown that structural differences in the intracellular domain of P2X receptors (P2XR) may determine the desensitization process. The lateral fenestrations of P2XR potentially serve as a pathway for ion conduction and play a decisive role in ion selectivity...

Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes...

Epilepsy, a condition characterized by spontaneous recurrent epileptic seizures, is among the most prevalent neurological disorders. This disorder is estimated to affect approximately 70 million people worldwide. Although antiseizure medications are considered the first-line treatments for epilepsy, most of the available antiepileptic drugs are not effective in nearly one-third of patients. This calls for the development of more effective drugs. Evidence from animal models and epilepsy patients suggests that strategies that interfere with the P2X7 receptor by binding to adenosine triphosphate (ATP) are potential treatments for this patient population...

At least four mechanisms have been proposed to elucidate how neurons in the retrotrapezoid (RTN) region sense changes in CO2 /H+ to regulate breathing (i.e., function as respiratory chemosensors). These mechanisms include: (1) intrinsic neuronal sensitivity to H+ mediated by TASK-2 and GPR4; (2) paracrine activation of RTN neurons by CO2 -responsive astrocytes (via a purinergic mechanism); (3) enhanced excitatory synaptic input or disinhibition; and (4) CO2 -induced vascular contraction. Although blood flow can influence tissue CO2 /H+ levels, there is limited understanding of how control of vascular tone in central CO2 chemosensitive regions might contribute to respiratory output...

Spinal cord injury can be traumatic or non-traumatic in origin, with the latter rising in incidence and prevalence with the aging demographics of our society. Moreover, as the global population ages, individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases, especially involving the cervical spinal cord. This makes recovery and treatment approaches particularly challenging as age and comorbidities may limit regenerative capacity. For these reasons, it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response...

The purinergic system has a dual role: the maintenance of energy balance and signaling within cells. Adenosine and adenosine triphosphate (ATP) are essential for maintaining these functions. Sarcopenia is characterized by alterations in the control of energy and signaling in favor of catabolic pathways. This review details the association between the purinergic system and muscle and adipose tissue homeostasis, discussing recent findings in the involvement of purinergic receptors in muscle wasting and advances in the use of the purinergic system as a novel therapeutic target in the management of sarcopenia...

Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation...

The elaborate mechanisms of depression have always been a research hotspot in recent years, and the pace of research has never ceased. The P2X7 receptor (P2X7R) belongs to one of the adenosine triphosphates (ATP)-gated cation channels that exist widely in brain tissues and play a prominent role in the regulation of depression-related pathology. To date, the role of purinergic P2X7R in the mechanisms underlying depression is not fully understood. In this review, we conclude that the purinergic receptor P2X7 is a potential therapeutic target for depression based on research results published over the past 5 years in Google Scholar and the National Library of Medicine (PubMed)...

Purinergic signaling has been associated with immune defenses against pathogens such as bacteria, protozoa, fungi, and viruses, acting as a sentinel system that signals to the cells when a threat is present. This review focuses on the roles of purinergic signaling and its therapeutic potential for viral infections. In this context, the purinergic system may play potent antiviral roles by boosting interferon signaling. In other cases, though, it can contribute to a hyperinflammatory response and disease severity, resulting in poor outcomes, such as during flu and potentially COVID-19...

BACKGROUND: Pain is a rapid response mechanism that compels organisms to retreat from the harmful stimuli and triggers a repair response. Nonetheless, when pain persists for extended periods, it can lead to adverse changes into in the individual's brain, negatively impacting their emotional state and overall quality of life. Microglia, the resident immune cells in the central nervous system (CNS), play a pivotal role in regulating a variety of pain-related disorders. Specifically, recent studies have shed light on the central role that microglial purinergic ligand-gated ion channel 7 receptor (P2X7R) plays in regulating pain...

The incidence of digestive malignancies has increased in recent years, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pancreatic cancer. Advanced stages of these cancers are prone to metastasis, which seriously reduce the standard of living of patients and lead to decline in the survival rate of patients. So far there are no good specific drugs to stop this phenomenon. It is very important and urgent to find new biomarkers and therapeutic targets. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is ATP-gated and nonselective ion channel receptor involved in many inflammatory processes and cancer progression...

Past studies have suggested that Chinese herbal may alleviate neuropathic pain, and the mechanism might target the inhibition of purinergic receptor P2. This review discusses whether traditional Chinese medicine target P2 receptors in neuropathic pain and its mechanism in order to provide references for future clinical drug development. The related literatures were searched from Pubmed, Embase, Sinomed, and CNKI databases before June 2023. The search terms included"neuropathic pain", "purinergic receptor P2", "P2", "traditional Chinese medicine", "Chinese herbal medicine", and "herb"...

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors (P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies...

The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PPi ) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy...

Since the late 1970s, there has been an alarming increase in the incidence of asthma and its morbidity and mortality. Acute obstruction and inflammation of allergic asthmatic airways are frequently caused by inhalation of exogenous substances such as allergens cross-linking IgE receptors expressed on the surface of the human lung mast cells (HLMC). The degree of constriction of human airways produced by identical amounts of inhaled allergens may vary from day to day and even hour to hour. Endogenous factors in the human mast cell (HMC)'s microenvironment during allergen exposure may markedly modulate the degranulation response...

Nucleosides and purine nucleotides serve as transmitter and modulator agents that extend their functions beyond the cell. In this context, purinergic signaling plays a crucial role in regulating energy homeostasis and modulating metabolic alterations in tumor cells. Therefore, it is essential to consider the pharmacological targeting of purinergic receptors (PUR), which encompass the expression and inhibition of P1 receptors (metabotropic adenosine receptors) as well as P2 receptors (extracellular ATP/ADP) comprising P2X and P2Y receptors...

Asthma is one of the main non-communicable chronic diseases and affects a huge portion of the population. It is a multifactorial disease, classified into several phenotypes, being the allergic the most frequent. The pathophysiological mechanism of asthma involves a Th2-type immune response, with high concentrations of allergen-specific immunoglobulin E, eosinophilia, hyperreactivity and airway remodeling. These mechanisms are orchestrated by intracellular signaling from effector cells, such as lymphocytes and eosinophils...

Purinergic signaling is a mechanism in which extracellular purines and pyrimidines interact with specialized cell surface receptors known as purinergic receptors. These receptors are divided into two families of P1 and P2 receptors, each responding to different nucleosides and nucleotides. P1 receptors are activated by adenosine, while P2 receptors are activated by pyrimidine and purines. P2X receptors are ligand-gated ion channels, including seven subunits (P2X1-7). However, P2Y receptors are the G-protein coupled receptors comprising eight subtypes (P2Y1/2/4/6/11/12/13/14)...

The pathogenesis of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), is complex and involves dysregulated immune responses, inflammation, and coagulopathy. Purinergic signaling, mediated by extracellular nucleotides and nucleosides, has emerged as a significant player in the pathogenesis of COVID-19. Extracellular adenosine triphosphate (ATP), released from damaged or infected cells, is a danger signal triggering immune responses. It activates immune cells, releasing pro-inflammatory cytokines, contributing to the cytokine storm observed in severe COVID-19 cases...

The P2X7 receptor (P2X7R) is an ATP-gated nonselective cationic channel that, upon intense stimulation, can progress to the opening of a pore permeable to molecules up to 900 Da. Apart from its broad expression in cells of the innate and adaptive immune systems, it is expressed in multiple cell types in different tissues. The dual gating property of P2X7R is instrumental in determining cellular responses, which depend on the expression level of the receptor, timing of stimulation, and microenvironmental cues, thus often complicating the interpretation of experimental data in comprehensive settings...