British Journal of Pharmacology最新文献

{"title":"Genetic variants linked to statin-associated Type 2 diabetes mellitus: Findings from the UK Biobank and the All of Us Research Program.","authors":"Yoon-A Park, Da Hoon Lee, Jung Sun Kim, Jeong Yee, Hye Sun Gwak","doi":"10.1111/bph.70164","DOIUrl":"https://doi.org/10.1111/bph.70164","url":null,"abstract":"<p><strong>Background and purpose: </strong>Statins are widely prescribed for the prevention of cardiovascular disease, yet recent studies suggest an increased risk of new-onset Type 2 diabetes mellitus. This study aimed to identify genetic variants associated with statin-associated new-onset Type 2 diabetes mellitus from the UK Biobank and All of Us.</p><p><strong>Experimental approach: </strong>Among statin users, cases were defined as those diagnosed with Type 2 diabetes mellitus after statin initiation and controls as those never having diabetes mellitus. A genome-wide association study (GWAS) was performed using logistic regression analysis with an additive model using the UK Biobank. We conducted a replication analysis in the All of Us cohort using the lead variants identified in the UK Biobank. Additionally, we tested interaction analyses between statin use and lead variants.</p><p><strong>Key results: </strong>The GWAS identified four significant lead variants. The most significant, TCF7L2 rs7903146, increased risk of new-onset Type 2 diabetes mellitus by 1.3-fold. Similarly, POU5F1 rs879882 was associated with a higher risk. By contrast, CCND2 rs76895963 and ADCY5 rs35841686 were associated with a lower risk. In the replication analysis of the All of Us cohort, TCF7L2 rs7903146, CCND2 rs76895963 and POU5F1 rs879882 remained significant. In the interaction analyses, those three lead variants also exhibited additive interactions with statin use.</p><p><strong>Conclusion and implications: </strong>These findings provide insights that may support personalized statin therapy to mitigate diabetic risk.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation, effects and monitoring of compartmented cGMP signalling in cardiomyocytes-current status.","authors":"Kjetil Wessel Andressen, Daiana Sedneva-Lugovets, Mette Ovesen, Ana Isabel Calejo, Dulasi Arunthavarajah, Finn Olav Levy","doi":"10.1111/bph.70144","DOIUrl":"https://doi.org/10.1111/bph.70144","url":null,"abstract":"<p><p>Cyclic guanosine 3',5'-monophosphate (cGMP) signalling in cardiomyocytes is intricately organized within cellular compartments, influencing several physiological and pathophysiological processes in the heart. We review how compartmented cGMP signalling is regulated and can be monitored within cardiomyocytes, emphasizing recent advances and methodologies. Three different guanylyl cyclases (GCs), two particulate (GC-A and GC-B) and one soluble (sGC), produce distinct cGMP pools, giving rise to differential signalling in cardiomyocytes. Phosphodiesterases (PDEs) maintain intracellular cGMP gradients. The use of intracellular biosensors, particularly those based on fluorescence resonance energy transfer (FRET), has enabled visualization of cGMP dynamics with high spatial and temporal resolution. These tools, which are constantly being improved, allow the observation of localized cGMP signals and have revealed discrete signalling compartments regulated by the subcellular localization of GCs and PDEs. Understanding these complex signalling networks in cardiomyocytes of healthy and diseased hearts can guide potential therapeutic approaches to treat cardiac dysfunction, including hypertrophy and heart failure. In conclusion, new tools are refining our understanding of compartmented cGMP signalling, which may lead to novel strategies for targeted therapeutic interventions in cardiovascular diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of chloride channels to the action potential and contraction in human myometrium during labour.","authors":"Helena C Parkington, Ranga E Siriwardhana, Mary A Tonta, Shaun P Brennecke, Penelope M Sheehan, Marianne Tare, Harold A Coleman","doi":"10.1111/bph.70146","DOIUrl":"https://doi.org/10.1111/bph.70146","url":null,"abstract":"<p><strong>Background and purpose: </strong>The action potential underpinning calcium delivery for contraction in human uterine smooth muscle (myometrium) consists of an initial spike(s) followed by a prolonged plateau of depolarization to ⁓ -25 mV. The plateau duration establishes contraction duration, especially important in labour. The purpose of this study was to determine the role of ANO1/TMEM16A chloride channels in the plateau.</p><p><strong>Experimental approach: </strong>Term human myometrial strips were obtained immediately following elective caesarean delivery before labour and during normally progressing labour. Contraction was recorded simultaneously with intracellular microelectrode recording of membrane potential. The chloride channel ANO1/TMEM16A was blocked using CaCC_inhib (5 𝜇M). Channel expression was probed via Western blotting.</p><p><strong>Key results: </strong>Myometrial strips were spontaneously contractile. The initial action potential spike(s) reflect the opening of voltage-gated calcium channels, since they were blocked by verapamil. The plateau, at -20 to 35 mV, had durations of 0.4 min before and 1.6 min during labour. CaCC_inhib abolished the plateau and markedly reduced contraction amplitude and duration. CaCC_inhib also reduced the ability of oxytocin, a vital labour hormone, to augment contraction. Western blotting revealed that myometrial ANO1 expression doubles in normal human labour.</p><p><strong>Conclusion and implications: </strong>The ANO1/TMEM16A chloride conductance 'clamps' the human myometrial membrane potential at a depolarized plateau, extending calcium influx and prolonging contraction, including that evoked by oxytocin. This function of ANO1 and its enhanced expression in labour are likely critical for the large and prolonged contractions required for expeditious birth of the offspring.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of monocarboxylate transporters in cancer immunology and their therapeutic potential","authors":"Ferdos Faghihkhorasani,&nbsp;Mona Moosavi,&nbsp;Al-Hasnawi Rasool Riyadh Abdulwahid,&nbsp;Mohammed Kavei,&nbsp;Soroush Karimi,&nbsp;Mahshid Seyed Karimi,&nbsp;Payam Vezvaei,&nbsp;Mahsa Manafi Varkiani,&nbsp;Amir Reza Aref,&nbsp;Nasim Ebrahimi","doi":"10.1111/bph.70110","DOIUrl":"10.1111/bph.70110","url":null,"abstract":"<p>Monocarboxylate transporters (MCTs) affect cancer metabolism and the regulation of immune responses, making them targets for cancer therapy. This study examines the roles of MCTs, specifically MCT1 and MCT4, in various cancer types and their influence on the advancement of tumours, metastasis and patient prognosis. We analyse the interaction among MCTs, tumour microenvironments (TMEs) and the immune system, as biomarkers and targets for therapy. Initial clinical trials have demonstrated encouraging outcomes with MCT inhibitors, including AZD3965. The combination of MCT inhibition and immunotherapy, such as immune checkpoint blockade, has shown synergistic effects in boosting the antitumour responses of the body's immune system. This study reviews the importance of MCTs and their potential as new targets for enhancing cancer therapy efficacy, especially when used in conjunction with current medicine treatment regimes. In numerous malignancies, tumour cells form a metabolic symbiosis wherein glycolytic cells, marked by elevated MCT4 expression, secrete lactate into the TME, while oxidative cancer cells, expressing MCT1, absorb this lactate as a metabolic substrate for the tricarboxylic acid cycle. Disrupting this lactate shuttle through targeted inhibition of MCTs is a promising strategy to overcome immune evasion and enhance the efficacy of immunotherapies. Targeting monocarboxylate transporters (MCTs) in glycolytic and oxidative tumour cells enhances antitumour immunity. Combinational therapy using MCT1 inhibitors (e.g. AZD3965), MCT4 inhibitors and immune checkpoint blockade can suppress lactate-mediated immunosuppression in the TME. By disrupting lactate shuttling between glycolytic and oxidative tumour cells, this strategy promotes T cell function and improves cancer treatment outcomes.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 19","pages":"4421-4457"},"PeriodicalIF":7.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IA-0130, a novel 3-(1,3-diarylallylidene)oxindole derivative, alleviates ovarian cancer via inhibiting IL-6/gp130/STAT3 signalling","authors":"Sun-Ae Park,&nbsp;Hee Jung Kim,&nbsp;Lee Kyung Kim,&nbsp;Hae-Ri Lee,&nbsp;Bo-Kyung Jung,&nbsp;Ji Hyeon Kim,&nbsp;Myung Jin Kim,&nbsp;Tae Gwon Oh,&nbsp;Hee Eun Kang,&nbsp;Kye Jung Shin,&nbsp;Jae Hong Seo,&nbsp;Tae-Hwe Heo","doi":"10.1111/bph.70142","DOIUrl":"10.1111/bph.70142","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Dysregulation of the IL-6/glycoprotein 130(gp130)/STAT3 signalling axis is implicated in several human diseases, particularly cancer. Notably, gp130, a single transducer of this signalling axis, is a target for ovarian cancer treatment. However, data regarding small-molecule inhibitors of gp130 are lacking. Therefore, we aimed to identify a 3-(1,3-diarylallylidene)oxindole derivative that binds gp130 and reveal the anticancer mechanism acting on the IL-6/gp130/STAT3 pathway in ovarian cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We synthesised 24 derivatives based on the scaffold of 3-(1,3-diarylallylidene)oxindole, and derivatives that inhibit IL-6 signalling were selected using HEK-Blue™ IL-6 cells. The binding of derivatives to gp130 was assessed using surface plasmon resonance. IA-0130, with a strong gp130-binding ability, was selected to observe its effect on the migration, invasion, cell cycle arrest and apoptosis of ovarian cancer cells in comparison to bazedoxifene, a known gp130-binding derivative. Additionally, we examined the mechanism underlying the tumour suppressive effect of IA-0130 in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that IA-0130 inhibited gp130/STAT3 phosphorylation in a concentration-dependent manner in ovarian cancer cell line and also in ovarian cancer-resistant cell line. By suppressing the expression of downstream target genes, IA-0130 inhibited cancer cell growth, metastasis, and invasion and induced apoptosis, exhibiting anticancer effects. In a mouse xenograft model of human ovarian cancer, oral administration of IA-0130 significantly delayed tumour growth.</p>\u0000 \u0000 <p>Conclusions and Implications</p>\u0000 \u0000 <p>IA-0130 inhibits tumour growth, migration and metastasis by inhibiting IL-6/gp130/STAT3 signalling in ovarian cancer by binding gp130. IA-0130 holds therapeutic potential for treating ovarian cancer as well as anticancer drug-resistant ovarian cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 22","pages":"5670-5689"},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis","authors":"Una Rastovic,&nbsp;Sara Campinoti,&nbsp;Lai Wei,&nbsp;Bruna Almeida,&nbsp;Sergio Francesco Bozzano,&nbsp;Ramin Amiri,&nbsp;Nicola Harris,&nbsp;Omolola Ajayi,&nbsp;Tsin Shue Koay,&nbsp;Caoimhe Kerins,&nbsp;Fiona N. Kenny,&nbsp;Ane Zamalloa,&nbsp;Lissette Adofina,&nbsp;Rosa Miquel,&nbsp;Yoh Zen,&nbsp;Parthi Srinivasan,&nbsp;Krishna Menon,&nbsp;Nigel Heaton,&nbsp;Camilla Luni,&nbsp;Eileen Gentleman,&nbsp;Tanya Shaw,&nbsp;Daren Ure,&nbsp;Shilpa Chokshi,&nbsp;Luca Urbani,&nbsp;Elena Palma","doi":"10.1111/bph.70139","DOIUrl":"10.1111/bph.70139","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Chronic liver disease and hepatic fibrosis constitute a threat to global health. Clinical translation of preclinical research has been limited, highlighting an urgent need for novel treatments. Cyclophilin inhibitors have shown beneficial effects in liver disease; however, the underlying mechanism of action and the effect across different aetiologies remain elusive. Here, we investigate the impact of a pan-cyclophilin inhibitor (rencofilstat, RCF) in human models of fibrosis and alcohol-related liver disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>RCF was tested in human precision-cut liver slices (PCLS) and primary human hepatic stellate cells (HSCs). Fibrosis and cell activation were assessed using transcriptomic and protein analysis. A comprehensive characterisation of changes in extracellular matrix (ECM) biochemical and structural composition was performed in PCLS and HSC-derived matrix using proteomics, imaging and bioinformatic tools to study ECM alignment. PCLS stiffness upon treatment was assessed by atomic force microscopy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Transcriptomic and proteomic analyses of PCLS revealed a dramatic impact of RCF on ECM organisation and remodelling. Biochemical composition and fibre alignment analysis of the ECM obtained from HSCs showed a reduction in the amount of ECM core proteins and associated enzymes by RCF, reshaping the architecture of matrix fibres without affecting the HSC activation. The disordered matrix detected in RCF-treated HSC cultures reflected a less-stiff ECM, which was confirmed in the PCLS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This work provides evidence for a novel mechanism linking cyclophilins and ECM remodelling in advanced 3D models of liver disease, with potential applications in therapeutic development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 22","pages":"5647-5669"},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are we hallucinating or can psychedelic drugs modulate the immune system to control inflammation?","authors":"Omar Qureshi, Jamie Cowley, Ashley Pegg, Alison J Cooper, John Gordon, Catherine A Brady, Antonio Belli, Sam Butterworth, Rachel Upthegrove, Nick Andrews, Nicholas M Barnes","doi":"10.1111/bph.70138","DOIUrl":"https://doi.org/10.1111/bph.70138","url":null,"abstract":"<p><p>Psychedelic drugs that activate 5-HT_2A receptors have been long used for cultural, medicinal and recreational purposes. Interest in psychedelics for treating psychiatric disorders has resurged recently and is well documented; less well recognised are their anti-inflammatory properties. Growing evidence now demonstrates that psychedelics modulate immune responses, including inhibiting pro-inflammatory cytokine release. Furthermore, in vivo studies demonstrate that psychedelics, like (R)-DOI, reduce inflammation in animal models of acute and chronic inflammatory disease such as asthma. Likewise, some clinical studies with psychedelic drugs (e.g. psilocybin) demonstrate an impact upon circulating cytokine levels, supporting a translation from the animal models to the clinical arena. Such data emphasise the promise of therapeutic approaches targeting inflammation. Interestingly, recent research has also uncovered compounds that maintain therapeutic potential without likely causing psychedelic effects. These discoveries suggest that drugs informed by psychedelic drugs, but which do not evoke psychedelic experiences, which we term PIPI drugs (Psychedelic drug Informed but Psychedelic experience Inactive), could offer effective treatments for mental health and inflammation, presenting new avenues for therapeutic development.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular hydrogen protects against sepsis-induced cardiomyopathy through improving Golgi stress-mediated autophagy, inflammation and apoptosis","authors":"Shuqi Meng,&nbsp;Jianfeng Liu,&nbsp;Yanhua Luo,&nbsp;Yan Fan,&nbsp;Zhiwei Wang,&nbsp;Yu Song,&nbsp;Shuaijie Pei,&nbsp;Xiaofan Huang,&nbsp;Lina Zhao,&nbsp;Keliang Xie","doi":"10.1111/bph.70132","DOIUrl":"10.1111/bph.70132","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Sepsis-induced cardiomyopathy (SIC) is the primary cause of mortality among people with sepsis. Hydrogen (H₂) has a cardioprotective effect in SIC; however, its specific mechanism remains unclear. We thus explored whether 2% H₂ treatment mitigates SIC through inhibiting Golgi stress and investigated the specific molecular pathways underlying this protective effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>Male C57BL/6J mice were subjected to caecal ligation and puncture (CLP) to establish the sepsis model. We measured the 7-day survival rates, cardiac function, myocardial damage enzymes, and myocardial haematoxylin and eosin (H&amp;E) staining to evaluate the 2% H₂ on SIC. Immunofluorescence and electron microscopy were used to observe the morphological changes in the Golgi apparatus (GA). Additionally, a Golgi stress-specific agonist (Brefeldin A) was administered to observe whether the therapeutic effect of inhalation of 2% H₂ could be reversed. Finally, we examined the indicators of autophagy, inflammation and apoptosis to explore how 2% H₂ affects the downstream mechanisms of Golgi stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The 7-day survival rate of mice decreased, cardiac function deteriorated and myocardial damage enzymes increased after CLP. Golgi stress was associated with elevated levels of autophagy, inflammation and apoptosis levels. These levels decreased following the treatment with 2% H₂ inhalation. However, administration of the Golgi stress-specific agonist Brefeldin A reversed the therapeutic effects of 2% H₂.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and implications</h3>\u0000 \u0000 <p>We found that 2% H₂ exerted a protective effect on SIC, and we determined that its mechanism is related to improving Golgi stress-mediated autophagy, inflammation and apoptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 22","pages":"5627-5646"},"PeriodicalIF":7.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compartmentalisation in cAMP signalling: A phase separation perspective.","authors":"Milda Folkmanaite, Manuela Zaccolo","doi":"10.1111/bph.70145","DOIUrl":"https://doi.org/10.1111/bph.70145","url":null,"abstract":"<p><p>Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase-mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid-liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase-mediated degradation. Disrupting LLPS-mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A procedure to identify persistent and effort-independent individual differences in preference for heroin over rewarding social interaction","authors":"Ginevra D'Ottavio,&nbsp;Alana Sullivan,&nbsp;Sara Pezza,&nbsp;Maria Chiara Ruano,&nbsp;Jacopo Modoni,&nbsp;Ingrid Reverte,&nbsp;Claudia Marchetti,&nbsp;Soami F. Zenoni,&nbsp;Marco Venniro,&nbsp;Michele S. Milella,&nbsp;Fernando Boix,&nbsp;Yavin Shaham,&nbsp;Daniele Caprioli","doi":"10.1111/bph.70125","DOIUrl":"10.1111/bph.70125","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>In some individuals, opioid use leads to decreased interest in socially relevant rewards. Recent studies showed that after extended-access heroin self-administration, rats strongly prefer social interaction over single unit-dose heroin infusions. We hypothesized that this strong social preference results from access to a suboptimal heroin dose during testing, and individual differences in heroin versus social choice would emerge if rats were given access to their ‘preferred’ heroin dose.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In Experiment 1, we trained male rats to lever-press for social interaction, followed by heroin self-administration under continuous-access, no-timeout schedule, which promotes burst-patterned heroin taking. We then tested the rats for choice between single-unit heroin dose and 1-min full-contact social interaction, or 5-min heroin-access (sufficient for burst-patterned heroin taking) and 5-min social interaction. In Experiment 2, we extended the 5-min access procedure to female rats and tested heroin versus limited-contact (screen-based) social interaction. We also manipulated response requirements (effort) for heroin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Rats given a single-unit heroin dose during choice testing, strongly preferred social interaction. In rats given 5-min heroin-access, large individual differences in heroin preference emerged. These differences were independent of sex, social-interaction conditions and effort manipulations. High heroin intake and burst-patterned heroin taking during self-administration, and high heroin seeking during abstinence predicted individual differences in heroin preference.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Access to ‘preferred’ heroin doses during the choice tests leads to stable and effort-independent individual differences in heroin preference. This procedure provides a platform to study mechanisms of resilience and vulnerability to opioid addiction.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 22","pages":"5596-5610"},"PeriodicalIF":7.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}