Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f37/2023.1
Valérie Audinot, Jean A. Boutin, Bernard Lakaye, Jean-Louis Nahon, Yumito Saito
Melanin-concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC-IUPHAR [32]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE.
{"title":"Melanin-concentrating hormone receptors in GtoPdb v.2023.1","authors":"Valérie Audinot, Jean A. Boutin, Bernard Lakaye, Jean-Louis Nahon, Yumito Saito","doi":"10.2218/gtopdb/f37/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f37/2023.1","url":null,"abstract":"Melanin-concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC-IUPHAR [32]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"133 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135017417","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f5/2023.1
Antonia Cianciulli, Liam Coulthard, Owen Hawksworth, John D. Lee, Xaria X. Li, Vincenzo Mitolo, Peter Monk, Maria A. Panaro, Trent M. Woodruff
Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [113]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a and C5a, generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3a receptor, C5a receptor 1 and C5a receptor 2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation.
{"title":"Complement peptide receptors in GtoPdb v.2023.1","authors":"Antonia Cianciulli, Liam Coulthard, Owen Hawksworth, John D. Lee, Xaria X. Li, Vincenzo Mitolo, Peter Monk, Maria A. Panaro, Trent M. Woodruff","doi":"10.2218/gtopdb/f5/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f5/2023.1","url":null,"abstract":"Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [113]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a and C5a, generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3a receptor, C5a receptor 1 and C5a receptor 2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"199 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135018169","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f98/2023.1
Derek Cain, John Cidlowski, Dean P. Edwards, Peter Fuller, Sandra L. Grimm, Sean Hartig, Carol A. Lange, Robert H. Oakley, Jennifer K. Richer, Carol A. Sartorius, Marc Tetel, Nancy Weigel, Morag J. Young
Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [75, 218, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.
{"title":"3C. 3-Ketosteroid receptors in GtoPdb v.2023.1","authors":"Derek Cain, John Cidlowski, Dean P. Edwards, Peter Fuller, Sandra L. Grimm, Sean Hartig, Carol A. Lange, Robert H. Oakley, Jennifer K. Richer, Carol A. Sartorius, Marc Tetel, Nancy Weigel, Morag J. Young","doi":"10.2218/gtopdb/f98/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f98/2023.1","url":null,"abstract":"Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [75, 218, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135018174","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f122/2023.1
Israel Hanukoglu
OverviewThe epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [10, 48, 14, 23, 22]. In these epithelia, Na+ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC and are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [42]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water [7]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [43]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [43, 32]. The genetics of the hereditary systemic pseudohypoaldosteronism type-I revealed that the activity of ENaC is dependent on three subunits encoded by three genes [23, 12]. Within the protein superfamily that includes ENaC, the crystal structure of ASIC was determined first, revealing a trimeric structure with a large extracellular domain anchored in the membrane with a bundle of six TM helices (two TM helices/subunit) [3, 26]. The first 3D structure of human ENaC was determined by single-particle cryo-electron microscopy at a resolution of 3.7 Å [38]. A recent study improved the resolution to 3 Å [39]. These structures confirmed that ENaC has a 3D quaternary structure similar to ASIC. ENaC is assembled as a hetero-trimer with a clockwise order of α-γ-β subunit viewed from the top, as shown previously [13]. In contrast to ASIC1 which can assemble into a functional homotrimer, ENaC activity can be reconstituted fully only as a heterotrimer with an αβγ or a δβγ composition [29]. In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [16]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [16]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on the non-cilial cell surface [16]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [48]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [48]. Thus, ENaC function regulates the volume of fluid lining epithelia essential for mucociliary clearance of respiratory airways, transp
ENaC活性受多种因素的调控，这些因素通过直接或间接地改变两个主要参数来发挥作用:1)膜中ENaC的密度;2)通道打开概率[27,29]。ENaC的Po被外部Na+大大降低，这种反应被称为Na+自抑制[49,4,25]。ENaC调控的一个重要方面是α和γ亚基在细胞外段具有保守的丝氨酸蛋白酶裂解位点[23]。furin和纤溶酶等蛋白酶对这些亚基的切割导致ENaC的激活[44,30,1]。与ENaC突变相关的疾病三种基因(SCNN1A、SCNN1B和SCNN1G)中的任何一种突变都可能导致ENaC活性的部分或完全丧失，这取决于突变[12,20]。这种功能丧失突变与一种名为“全身性”或“多系统”常染色体隐性假醛固酮增多症I型(PHA1B)的综合征有关[19,12,23,16,55,46]。到目前为止，还没有在SCNN1D基因中发现导致PHA的突变。PHA患者在表达ENaC的所有醛固酮靶器官(包括肾脏、汗腺、唾液腺和呼吸道)均存在严重的盐流失。在婴儿期和幼儿期，严重的电解质紊乱、脱水和酸中毒可能需要反复住院。盐耗发作的严重程度和频率随着年龄的增长而提高[21]。PHA1B也与女性生殖系统功能失调有关[16,6]。ENaC的羧基端包含一个短的一致序列，称为PY基序。SCNN1B和SCNN1G中该基序的突变与Liddle综合征有关，Liddle综合征以早发性高血压为特征[5,50]。PY基序被一种泛素连接酶Nedd4-2识别。因此，PY基序的突变降低ENaC的泛素化，导致ENaC在膜中积累，从而增强ENaC的活性[45]。ENaC在肿瘤中的表达观察到[Na+]在许多癌细胞中的表达高于非癌细胞，这提示ENaC表达的增强可能是导致转移增加的原因[33]。然而，对来自The cancer Genome Atlas的enact编码基因的RNA测序数据和宫颈癌患者的临床数据分析显示，enact编码基因与肿瘤的组织学分级呈负相关[51]。同样，对通过过表达或sirna介导的敲低改变α-ENaC水平的乳腺癌细胞的研究表明，α-ENaC表达增加与乳腺癌细胞增殖降低相关[54]。相反，对The Cancer Genome Atlas RNA测序数据的分析显示，SCNN1A高表达与卵巢癌患者预后不良相关[35]。这些发现表明ENaC水平与肿瘤发生的关系因组织而异。导致COVID-19的SARS-CoV-2病毒粒子表面被许多糖基化S(刺突)蛋白覆盖。这些S蛋白与膜结合的血管紧张素转换酶2 (ACE2)结合，作为病毒粒子进入宿主细胞的第一步。病毒进入细胞依赖于丝氨酸蛋白酶对S蛋白(Arg-667/Ser-668)的切割。Anand等研究表明，该裂解位点具有与α-ENaC中furin裂解位点同源的序列基序[2]。对COVID-19病理后果的综合综述表明，ENaC在COVID-19感染呼吸道上皮的早期阶段发挥了作用[17]。
{"title":"Epithelial sodium channel (ENaC) in GtoPdb v.2023.1","authors":"Israel Hanukoglu","doi":"10.2218/gtopdb/f122/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f122/2023.1","url":null,"abstract":"OverviewThe epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [10, 48, 14, 23, 22]. In these epithelia, Na+ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC and are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [42]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water [7]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [43]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [43, 32]. The genetics of the hereditary systemic pseudohypoaldosteronism type-I revealed that the activity of ENaC is dependent on three subunits encoded by three genes [23, 12]. Within the protein superfamily that includes ENaC, the crystal structure of ASIC was determined first, revealing a trimeric structure with a large extracellular domain anchored in the membrane with a bundle of six TM helices (two TM helices/subunit) [3, 26]. The first 3D structure of human ENaC was determined by single-particle cryo-electron microscopy at a resolution of 3.7 Å [38]. A recent study improved the resolution to 3 Å [39]. These structures confirmed that ENaC has a 3D quaternary structure similar to ASIC. ENaC is assembled as a hetero-trimer with a clockwise order of α-γ-β subunit viewed from the top, as shown previously [13]. In contrast to ASIC1 which can assemble into a functional homotrimer, ENaC activity can be reconstituted fully only as a heterotrimer with an αβγ or a δβγ composition [29]. In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [16]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [16]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on the non-cilial cell surface [16]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [48]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [48]. Thus, ENaC function regulates the volume of fluid lining epithelia essential for mucociliary clearance of respiratory airways, transp","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73513945","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f214/2023.1
A. Stahl
Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six [6, 13], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [4, 10, 11]. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.- , EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids [9, 13, 1].
{"title":"SLC27 family of fatty acid transporters in GtoPdb v.2023.1","authors":"A. Stahl","doi":"10.2218/gtopdb/f214/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f214/2023.1","url":null,"abstract":"Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six [6, 13], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [4, 10, 11]. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.- , EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids [9, 13, 1].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77588286","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f95/2023.1
M. Tsai, S. Tsai
COUP-TF-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7, 2]) have yet to be officially paired with an endogenous ligand.
{"title":"2F. COUP-TF-like receptors in GtoPdb v.2023.1","authors":"M. Tsai, S. Tsai","doi":"10.2218/gtopdb/f95/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f95/2023.1","url":null,"abstract":"COUP-TF-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7, 2]) have yet to be officially paired with an endogenous ligand.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"24 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91480844","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f64/2023.1
T. Bonner, A. Davenport, S. Foord, J. Maguire, William A. E. Parker
Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [9], where 15 mammalian orthologues were identified and divided into two families. The TA1 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [58]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [9]. Emerging evidence suggests that TA1 is a modulator of monoaminergic activity in the brain [94] with TA1 and dopamine D2 receptors shown to form constitutive heterodimers when co-expressed [30]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines.
{"title":"Trace amine receptor in GtoPdb v.2023.1","authors":"T. Bonner, A. Davenport, S. Foord, J. Maguire, William A. E. Parker","doi":"10.2218/gtopdb/f64/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f64/2023.1","url":null,"abstract":"Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [9], where 15 mammalian orthologues were identified and divided into two families. The TA1 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [58]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [9]. Emerging evidence suggests that TA1 is a modulator of monoaminergic activity in the brain [94] with TA1 and dopamine D2 receptors shown to form constitutive heterodimers when co-expressed [30]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84885414","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f238/2023.1
B. Hagenbuch
The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.
{"title":"SLCO family of organic anion transporting polypeptides in GtoPdb v.2023.1","authors":"B. Hagenbuch","doi":"10.2218/gtopdb/f238/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f238/2023.1","url":null,"abstract":"The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88448060","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f236/2023.1
Ken-ichi Inui
Human multidrug and toxin extrusion MATE1 and MATE2-K are H+/organic cation antiporters [1]. They are predominantly expressed in the kidney and play a role in renal tubular secretion of cationic drugs.
{"title":"SLC47 family of multidrug and toxin extrusion transporters in GtoPdb v.2023.1","authors":"Ken-ichi Inui","doi":"10.2218/gtopdb/f236/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f236/2023.1","url":null,"abstract":"Human multidrug and toxin extrusion MATE1 and MATE2-K are H+/organic cation antiporters [1]. They are predominantly expressed in the kidney and play a role in renal tubular secretion of cationic drugs.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135016699","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}
Pub Date : 2023-04-26DOI: 10.2218/gtopdb/f25/2023.1
Elisa Arthofer, Jacomijn Dijksterhuis, Lukas Grätz, Belma Hot, Paweł Kozielewicz, Matthias Lauth, Jessica Olofsson, Julian Petersen, Tilman Polonio, Gunnar Schulte, Katerina Strakova, Jana Valnohova, Shane Wright
Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [180]), are GPCRs originally identified in Drosophila [20], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [180]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [186, 6, 58]. While SMO itself is bound by sterols and oxysterols [27, 94], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [138]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [34, 183, 155], the elevation of intracellular calcium [189], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [57]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [244, 245, 107, 179, 104]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [245]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [23], as well as for β-catenin-dependent [14] and -independent [91, 15] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.
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