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Fluoride Transport and Inhibition Across CLC Transporters. 氟的转运和对 CLC 转运体的抑制。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2022_593
Somayeh Asgharpour, L América Chi, Marc Spehr, Paolo Carloni, Mercedes Alfonso-Prieto
{"title":"Fluoride Transport and Inhibition Across CLC Transporters.","authors":"Somayeh Asgharpour, L América Chi, Marc Spehr, Paolo Carloni, Mercedes Alfonso-Prieto","doi":"10.1007/164_2022_593","DOIUrl":"10.1007/164_2022_593","url":null,"abstract":"<p><p>The Chloride Channel (CLC) family includes proton-coupled chloride and fluoride transporters. Despite their similar protein architecture, the former exchange two chloride ions for each proton and are inhibited by fluoride, whereas the latter efficiently transport one fluoride in exchange for one proton. The combination of structural, mutagenesis, and functional experiments with molecular simulations has pinpointed several amino acid changes in the permeation pathway that capitalize on the different chemical properties of chloride and fluoride to fine-tune protein function. Here we summarize recent findings on fluoride inhibition and transport in the two prototypical members of the CLC family, the chloride/proton transporter from Escherichia coli (CLC-ec1) and the fluoride/proton transporter from Enterococcus casseliflavus (CLC<sup>F</sup>-eca).</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"81-100"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10442359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction to: Fluoride Transport and Inhibition Across CLC Transporters. 更正：氟的转运和对 CLC 转运体的抑制。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2022_620
Somayeh Asgharpour, L América Chi, Marc Spehr, Paolo Carloni, Mercedes Alfonso-Prieto
{"title":"Correction to: Fluoride Transport and Inhibition Across CLC Transporters.","authors":"Somayeh Asgharpour, L América Chi, Marc Spehr, Paolo Carloni, Mercedes Alfonso-Prieto","doi":"10.1007/164_2022_620","DOIUrl":"10.1007/164_2022_620","url":null,"abstract":"","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"361-362"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10447956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ClC-K Kidney Chloride Channels: From Structure to Pathology. ClC-K 肾脏氯离子通道：从结构到病理
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2023_635
Olga Andrini, Dominique Eladari, Nicolas Picard
{"title":"ClC-K Kidney Chloride Channels: From Structure to Pathology.","authors":"Olga Andrini, Dominique Eladari, Nicolas Picard","doi":"10.1007/164_2023_635","DOIUrl":"10.1007/164_2023_635","url":null,"abstract":"<p><p>The molecular basis of chloride transport varies all along the nephron depending on the tubular segments especially in the apical entry of the cell. The major chloride exit pathway during reabsorption is provided by two kidney-specific ClC chloride channels ClC-Ka and ClC-Kb (encoded by CLCNKA and CLCNKB gene, respectively) corresponding to rodent ClC-K1 and ClC-K2 (encoded by Clcnk1 and Clcnk2). These channels function as dimers and their trafficking to the plasma membrane requires the ancillary protein Barttin (encoded by BSND gene). Genetic inactivating variants of the aforementioned genes lead to renal salt-losing nephropathies with or without deafness highlighting the crucial role of ClC-Ka, ClC-Kb, and Barttin in the renal and inner ear chloride handling. The purpose of this chapter is to summarize the latest knowledge on renal chloride structure peculiarity and to provide some insight on the functional expression on the segments of the nephrons and on the related pathological effects.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"35-58"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10759212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Looking to the Future: Drug Delivery and Targeting in the Prophylaxis and Therapy of Severe and Chronic Diseases. 展望未来：药物递送和靶向在严重和慢性疾病的预防和治疗中。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2023_696
Monika Schäfer-Korting
{"title":"Looking to the Future: Drug Delivery and Targeting in the Prophylaxis and Therapy of Severe and Chronic Diseases.","authors":"Monika Schäfer-Korting","doi":"10.1007/164_2023_696","DOIUrl":"10.1007/164_2023_696","url":null,"abstract":"<p><p>High molecular weight actives and cell-based therapy have the potential to revolutionize the prophylaxis and therapy of severe diseases. Yet, the size and nature of the agents - proteins, nucleic acids, cells - challenge drug delivery and thus formulation development. Moreover, off-target effects may result in severe adverse drug reactions. This makes delivery and targeting an essential component of high-end drug development. Loading to nanoparticles facilitates delivery and enables targeted mRNA vaccines and tumor therapeutics. Stem cell therapy opens up a new horizon in diabetes type 1 among other domains which may enhance the quality of life and life expectancy. Cell encapsulation protects transplants against the recipient's immune system, may ensure long-term efficacy, avoid severe adverse reactions, and simplify the management of rare and fatal diseases.The knowledge gained so far encourages to widen the spectrum of potential indications. Co-development of the active agent and the vehicle has the potential to accelerate drug research. One recommended starting point is the use of computational approaches. Transferability of preclinical data to humans will benefit from performing studies first on validated human 3D disease models reflecting the target tissue, followed by studies on validated animal models. This makes approaching a new level in drug development a multidisciplinary but ultimately worthwhile and attainable challenge. Intense monitoring of the patients after drug approval and periodic reporting to physicians and scientists remain essential for the safe use of drugs especially in rare diseases and pave future research.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"389-411"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49676802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Stimuli-Responsive Non-viral Nanoparticles for Gene Delivery. 用于基因递送的刺激响应性非病毒纳米粒子。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2023_694
Liên S Reichel, Anja Traeger
{"title":"Stimuli-Responsive Non-viral Nanoparticles for Gene Delivery.","authors":"Liên S Reichel, Anja Traeger","doi":"10.1007/164_2023_694","DOIUrl":"10.1007/164_2023_694","url":null,"abstract":"<p><p>Considering nucleic acids as the language of life and the genome as the instruction manual of cells, their targeted modulation promises great opportunities in treating and healing diseases. In addition to viral gene transfer, the overwhelming power of non-viral mRNA-based vaccines is driving the development of novel gene transporters. Thereby, various nucleic acids such as DNA (pDNA) or RNA (mRNA, siRNA, miRNA, gRNA, or ASOs) need to be delivered, requiring a transporter due to their high molar mass and negative charge in contrast to classical agents. This chapter presents the specific biological hurdles for using nucleic acids and shows how new materials can overcome these.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"27-43"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10468229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adrenoceptors in the Lower Urinary Tract. 下尿路的肾上腺素受体
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2023_678
Martin Hennenberg, Martin C Michel
{"title":"Adrenoceptors in the Lower Urinary Tract.","authors":"Martin Hennenberg, Martin C Michel","doi":"10.1007/164_2023_678","DOIUrl":"10.1007/164_2023_678","url":null,"abstract":"<p><p>Adrenoceptors importantly contribute to the physiological regulation of lower urinary tract (LUT) function and have become a target of several clinically successful treatments for major LUT diseases. In the bladder dome, β-adrenoceptor subtypes are found in multiple cell types and mediate relaxation of detrusor smooth muscle, perhaps partly indirectly by acting on afferent nerves and cells of the mucosa. β<sub>3</sub>-adrenoceptor agonists such as mirabegron and vibegron are used to treat overactive bladder syndrome. In the bladder trigone and urethra, α<sub>1</sub>-adrenoceptors cause contraction and thereby physiologically contribute to bladder outlet resistance. α<sub>1</sub>-adrenoceptors in the prostate also cause contraction and pathophysiologically elevate bladder outlet resistance leading to voiding dysfunction in benign prostatic hyperplasia. α<sub>1</sub>-adrenoceptor antagonist such as tamsulosin is widely used as a first-line option to treat LUT symptoms in men, but it remains unclear to which extent and how smooth muscle relaxation contributes to symptom relief.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"333-367"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9771229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adrenoceptor Expression and Function in the Endocrine Pancreas. 内分泌胰腺中肾上腺素受体的表达和功能
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2024_717
Haneen Dwaib, Martin C Michel
{"title":"Adrenoceptor Expression and Function in the Endocrine Pancreas.","authors":"Haneen Dwaib, Martin C Michel","doi":"10.1007/164_2024_717","DOIUrl":"10.1007/164_2024_717","url":null,"abstract":"<p><p>The sympathetic nervous system plays an important role in the regulation of endocrine pancreatic function, most importantly insulin release. Among the nine adrenoceptor (AR) subtypes, the α<sub>2A</sub>-AR appears to be the subtype most abundantly expressed in the human pancreas. While α<sub>2</sub>- and β-AR have opposing effects, the net response to sympathetic stimulation is inhibition of insulin secretion mediated by α<sub>2</sub>-AR located in the plasma membrane of pancreatic β cells. This inhibition may be present physiologically as evidenced by increased insulin secretion in healthy and diabetic humans and animals in response to α<sub>2</sub>-AR antagonists, a finding that was confirmed in all studies. Based on such data and on an association of an α<sub>2A</sub>-AR polymorphism, that increases receptor expression levels, with an elevated risk for diabetes, increased α<sub>2A</sub>-AR signaling in the pancreatic β cells has been proposed as a risk factor for the development of type 2 diabetes. Thus, the α<sub>2A</sub>-AR was proposed as a drug target for the treatment of some forms of type 2 diabetes. Drug research and development programs leveraging this mechanism have reached the clinical stage, but none have resulted in an approved medicine due to a limited efficacy. While β-AR agonists can increase circulating insulin levels in vivo, it remains controversial whether this includes a direct effect on β cells or occurs secondary to general metabolic effects. Therefore, the regulation of endocrine pancreatic function is physiologically interesting but may be of limited therapeutic relevance.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"639-664"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adrenoceptors: Receptors, Ligands and Their Clinical Uses, Molecular Pharmacology and Assays. 肾上腺素受体：肾上腺素受体：受体、配体及其临床应用，分子药理学与检测。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2024_713
Jillian G Baker, Roger J Summers
{"title":"Adrenoceptors: Receptors, Ligands and Their Clinical Uses, Molecular Pharmacology and Assays.","authors":"Jillian G Baker, Roger J Summers","doi":"10.1007/164_2024_713","DOIUrl":"10.1007/164_2024_713","url":null,"abstract":"<p><p>The nine G protein-coupled adrenoceptor subtypes are where the endogenous catecholamines adrenaline and noradrenaline interact with cells. Since they are important therapeutic targets, over a century of effort has been put into developing drugs that modify their activity. This chapter provides an outline of how we have arrived at current knowledge of the receptors, their physiological roles and the methods used to develop ligands. Initial studies in vivo and in vitro with isolated organs and tissues progressed to cell-based techniques and the use of cloned adrenoceptor subtypes together with high-throughput assays that allow close examination of receptors and their signalling pathways. The crystal structures of many of the adrenoceptor subtypes have now been determined opening up new possibilities for drug development.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"55-145"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141456360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CFTR Modulators: From Mechanism to Targeted Therapeutics. CFTR 调节剂：从机制到靶向治疗。
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2022_597
Han-I Yeh, Katy J Sutcliffe, David N Sheppard, Tzyh-Chang Hwang
{"title":"CFTR Modulators: From Mechanism to Targeted Therapeutics.","authors":"Han-I Yeh, Katy J Sutcliffe, David N Sheppard, Tzyh-Chang Hwang","doi":"10.1007/164_2022_597","DOIUrl":"10.1007/164_2022_597","url":null,"abstract":"<p><p>People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"219-247"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40701018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A). 钙激活氯离子通道 Anoctamin 1 (TMEM16A) 的功能与调控
Handbook of experimental pharmacology Pub Date : 2024-01-01 DOI: 10.1007/164_2022_592
Jorge Arreola, Patricia Pérez-Cornejo, Guadalupe Segura-Covarrubias, Nancy Corral-Fernández, Daniel León-Aparicio, María Luisa Guzmán-Hernández
{"title":"Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A).","authors":"Jorge Arreola, Patricia Pérez-Cornejo, Guadalupe Segura-Covarrubias, Nancy Corral-Fernández, Daniel León-Aparicio, María Luisa Guzmán-Hernández","doi":"10.1007/164_2022_592","DOIUrl":"10.1007/164_2022_592","url":null,"abstract":"<p><p>Various human tissues express the calcium-activated chloride channel Anoctamin 1 (ANO1), also known as TMEM16A. ANO1 allows the passive chloride flux that controls different physiological functions ranging from muscle contraction, fluid and hormone secretion, gastrointestinal motility, and electrical excitability. Overexpression of ANO1 is associated with pathological conditions such as hypertension and cancer. The molecular cloning of ANO1 has led to a surge in structural, functional, and physiological studies of the channel in several tissues. ANO1 is a homodimer channel harboring two pores - one in each monomer - that work independently. Each pore is activated by voltage-dependent binding of two intracellular calcium ions to a high-affinity-binding site. In addition, the binding of phosphatidylinositol 4,5-bisphosphate to sites scattered throughout the cytosolic side of the protein aids the calcium activation process. Furthermore, many pharmacological studies have established ANO1 as a target of promising compounds that could treat several illnesses. This chapter describes our current understanding of the physiological roles of ANO1 and its regulation under physiological conditions as well as new pharmacological compounds with potential therapeutic applications.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"101-151"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40409504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
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