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Calcium activated chloride channel (CaCC) in GtoPdb v.2025.3
Full text linkChloride channels activated by intracellular Ca2+ (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [25]. CaCCs are activated by a rise in intracellular free Ca2+ concentration ([Ca2+]i), typically following activation of Gq protein coupled receptors (GqPCR). This section centres on CaCC channels encoded by the TMEM16A gene (HUGO gene nomenclature: Anoctamin 1). The TMEM16 family consists of 10 paralogs (TMEM16A-K; Anoctamin 1-10). The TMEM16A and TMEM16B genes (ANO1 and ANO2) encode for CaCCs, while the other members function as lipid scramblases or have combined scramblase and non-selective ion channel function [26, 46, 18, 1, 41]. TMEM16A has a broad tissue distribution and a variety of established cellular roles, while the main physiological role for TMEM16B identified thus far is in olfaction [31, 16]. Alternative splicing regulates the voltage- and Ca2+-dependence of TMEM16A and such post-transcriptional process may be tissue-specific and contribute to functional diversity [19]. TMEM16A is a potential drug target for a variety of conditions spanning from respiratory to vascular (see "Comments" section for further detail)
ABCB subfamily in GtoPdb v.2025.3
No full textThe ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [8, 1]
ABCG subfamily in GtoPdb v.2025.3
Full text linkThis family of \u27half-transporters\u27 act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [6], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [13, 1]
Adenylyl cyclases (ACs) in GtoPdb v.2025.3
Full text linkAdenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [11]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gαs (the stimulatory G protein α subunit) and forskolin (except AC9, [29]). adenosine and its derivatives (e.g. 2\u27,5\u27-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [36]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca2+- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca2+-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [7]
Pattern recognition receptors in GtoPdb v.2025.3
Full text linkPattern Recognition Receptors (PRRs, [118]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [21]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE
Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family in GtoPdb v.2025.3
Full text linkVEGF receptors are homo- and heterodimeric proteins, which are characterized by seven Ig-like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non-signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA is able to activate VEGFR1 and VEGFR2 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB and placental growth factor activate VEGFR1 homodimers, while VEGFC and VEGFD activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers
S33: Prolyl aminopeptidase in GtoPdb v.2025.3
Full text linkPeptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides
SLC54 Mitochondrial pyruvate carriers in GtoPdb v.2025.3
Full text linkThe mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 or MPC1L and MPC2) [1, 5, 10], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and is responsible for the import of pyruvate into mitochondria [1, 5]. Pyruvate is oxidized to acetyl-CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [11, 12]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [3]. Other clinically relevant inhibitors of the MPC complex are lonidamine [7, 8], quinolone antibacterials [6], entacapone and nitrofurantoin [8]
Epithelial sodium channel (ENaC) in GtoPdb v.2025.4
Full text linkOverviewEpithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lungs, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and several other organs [10, 17, 26, 25, 57]. In these epithelia, Na+ ions enter epithelial cells from the extracellular fluid via ENaC and are subsequently pumped out into the interstitial fluid by the Na+/K+-ATPase on the basolateral membrane [49]. Because sodium is a major electrolyte in the extracellular fluid (ECF), the osmotic changes caused by sodium flux are accompanied by parallel water movement [7]. Thus, ENaC plays a central role in regulating ECF volume and blood pressure, primarily through its function in the kidney [51]. The expression of ENaC subunits- and therefore its activity- is controlled by the renin-angiotensin-aldosterone system and other factors involved in electrolyte homeostasis [51, 36]. Genetic studies of systemic pseudohypoaldosteronism type I revealed that ENaC activity depends on three essential subunits encoded by three separate genes encoding homologous proteins [12, 26]. Within the wider protein superfamily that includes ENaC, the first crystal structure determined was that of ASIC, which revealed a trimeric structure with a large extracellular domain anchored in the membrane by a bundle of six transmembrane helices (two per subunit) [3, 30]. The first 3D structure of human ENaC was determined using single-particle cryo-electron microscopy at 3.7Å resolution [45], later improved to 3.0Å [46]. These structures confirmed that ENaC has a quaternary structure similar to ASIC. ENaC assembles as a heterotrimer, with α-, γ-, and β-subunits arranged in clockwise order when viewed from above [13]. In contrast to ASIC1, which can form a functional homotrimer, ENaC is only fully functional as a heterotrimer composed of either αβγ or δβγ [33]. Recently, Houser and Baconguis co-expressed human δ, β, and γ and determined the structures of complexes using single-particle cryoelectron microscopy. The structures showed that β and γ positions are conserved among the different complexes while the α position in the αβγ trimer is occupied by either δ or another β [29]. In the respiratory and female reproductive tracts, large regions of the epithelium consist of multiciliated cells with a microtubule-based cytoskeleton. In these cells, ENaC is distributed along the entire length of the cilia [19]. This localization substantially increases ENaC density on the cell surface and enables precise regulation of periciliary fluid osmolarity throughout its depth [19]. In the vas deferens of the male reproductive tract, the luminal surface is covered with microvilli and stereocilia supported by actin bundles [57]. In these cells, both ENaC and the aquaporin AQP9 are localized to the projections as well as to the basal and smooth muscle layers [57]. In contrast, CFTR- the chloride channel defective in cystic fibrosis- is confined to the apical cell surface but is absent from cilia and microvilli [19, 57]. Collectively, ENaC function regulates epithelial fluid volume, which is essential for mucociliary clearance in the respiratory tract, gamete transport, fertilization, implantation, and cell migration [19, 44, 26]. Genes and PhylogenyThe human genome contains four homologous genes (SCNN1A, SCNN1B, SCNN1G, and SCNN1D) encoding the α-, β-, γ-, and δ-ENaC subunits, respectively [11, 40, 55, 62]. These subunits share 23–34% sequence identity and <20% identity with ASIC subunits [26]. Genes encoding all four ENaC subunits are present in bony vertebrates, except in ray-finned fishes, which have lost them entirely. The mouse genome has also lost SCNN1D, the gene for δ-ENaC [21, 26]. The α-, β-, and γ-ENaC genes are present in jawless vertebrates (e.g., lampreys) and cartilaginous fishes (e.g., sharks) [26]. Methylation analysis of the 5′-flanking regions of SCNN1A, SCNN1B, and SCNN1G in human cells revealed an inverse correlation between gene expression and DNA methylation, suggesting epigenetic transcriptional control of ENaC genes [48]. Channel biogenesis, assembly and functionENaC subunit expression is regulated primarily by aldosterone and by numerous other extracellular and intracellular factors [51, 35, 47]. Most studies indicate that expression of the three subunits is not tightly coordinated [9]. However, transport of the subunits to the membrane requires all three intact subunits, and even a single missense mutation can reduce the number of assembled channels on the cell surface [18]. ENaC is constitutively active, meaning Na+ flow does not require an activating factor. Thus, heterologous cells expressing ENaC (e.g., human cRNAs in Xenopus oocytes) must be maintained in amiloride-containing solutions to block channel activity. ENaC activity is then measured by replacing the bath with amiloride-free solution. The channel alternates between two states: 1) open and 2) closed. The probability of ENaC being open is referred to as open probability (Po). ENaC regulation involves two key parameters: (1) membrane channel density and (2) open probability [31, 33]. Open probability is markedly reduced by extracellular Na+ in a process known as sodium self-inhibition [4, 28, 59]. A key regulatory feature is that the α- and γ-subunits contain conserved extracellular serine protease cleavage sites [26]. Proteolytic cleavage by enzymes such as furin and plasmin activates ENaC [52, 34, 1]. Diseases associated with ENaC mutationsMutations in SCNN1A, SCNN1B, or SCNN1G can cause partial or complete loss of ENaC activity [12, 23]. Such loss-of-function mutations are associated with systemic or multi-system autosomal recessive pseudohypoaldosteronism type I (OMIM abbreviation: PHA1B) [22, 12, 26, 64, 19, 54]. No PHA-causing mutations have been identified in SCNN1D. Patients with PHA experience severe salt wasting in all aldosterone target organs expressing ENaC, including kidney, sweat glands, salivary glands, and respiratory tract. In infancy and early childhood, the resulting electrolyte disturbances, dehydration, and acidosis often require recurrent hospitalization. The frequency and severity of salt-wasting episodes generally improve with age [24]. PHA1B also affects female reproductive system function [19, 6]. The ENaC carboxy-terminal region contains a short consensus sequence called the PY motif. Mutations in this motif in SCNN1B and SCNN1G are associated with Liddle syndrome, a disorder marked by early-onset hypertension [60, 5]. The PY motif is recognized by Nedd4-2, a ubiquitin ligase. Mutations that disrupt this recognition reduce ENaC ubiquitylation, leading to channel accumulation at the membrane and increased ENaC activity [53]. ENaC expression in tumorsIntracellular sodium concentrations are often elevated in cancer cells compared with normal cells, leading to the hypothesis that ENaC overexpression may contribute to metastasis [39]. However, RNA-seq analysis of ENaC genes and clinical data of cervical cancer patients from The Cancer Genome Atlas (TCGA) revealed a negative correlation with histologic grades of tumor [61]. Similarly, in breast cancer cells, overexpression or siRNA-mediated knockdown of α-ENaC showed that higher α-ENaC levels suppress cell proliferation [63]. In contrast, TCGA data showed that elevated SCNN1A expression correlates with poor prognosis in ovarian cancer [41]. Thus, the role of ENaC in tumorigenesis appears to be tissue-specific. COVID-19SARS-CoV-2 virions, the cause of COVID-19, are covered with glycosylated spike (S) proteins. These proteins bind to membrane-bound ACE2 as the first step of viral entry. Entry depends on S-protein cleavage (at Arg-667/Ser-668) by a serine protease. Anand et al. identified a sequence motif at this cleavage site homologous to the furin cleavage site in ENaCα [2]. A comprehensive review of COVID-19 pathophysiology suggests a role for ENaC in the early stages of infection in respiratory epithelia [20]. ENaC Inhibitors for Cystic Fibrosis Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disorder among Caucasians. CF is caused by mutations in the gene that codes for CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). CFTR is a chloride and bicarbonate channel located on the apical membrane [14]. CFTR-mediated movement of Cl- and HCO3- ions into the lumen also drives water flow into the lumen by osmosis. CFTR is expressed in many tissues but the most severe effect of mutated CFTR is observed in the respiratory tract in the form of airway surface liquid (ASL) depletion which leads to mucus accumulation, inflammation and bacterial infections that lead to mortality. Normal CFTR activity inhibits ENaC by causing a reduction in surface expression of ENaC as well as its Po [50]. In many epithelia, ENaC and CFTR are not co-localized on the apical membrane indicating that the two channels do not directly interact [19, 56, 57]. In the absence of a functional CFTR, ENaC activity increases (also named as "hyperactivated ENaC"), leading to increased Na+ and water absorption and consequently ASL depletion. These observations have led to the development of inhibitors targeting ENaC in the airways to ameliorate ASL dehydration [58, 43, 38]. Most of the ENaC inhibitors in development are designed for application by inhalation and improved lung retention to avoid damaging the vital activity of ENaC in other tissues [37, 16]. Despite the development of many ENaC inhibitors for CF [15], nearly all drug candidates were discontinued at Preclinical, Phase 1 or Phase 2 stage of clinical trials [38, 16, 43]. However, there is one candidate, EDT001, that is still under Phase 2 clinical trial [16]. The persistence of the scientists and the drug companies and the versatility of their approaches provide hope that an appropriate useful treatment will emerge to help CF patients. Thus, insights into the physiological and pathological roles of ENaC across diverse tissues continue to guide the development of targeted inhibitors, with cystic fibrosis representing a prominent example where modulation of ENaC activity may translate fundamental biology into therapeutic benefit
“If I Have Nothing to Hide, I Have Nothing to Fear”: privacy, public and private surveillance in the digital age by Jared Higgins
No full textThe \u27nothing to hide\u27 argument has been described as the \u27most common retort against privacy advocates\u27: suggesting that state surveillance only threatens criminals, and ordinary, law-abiding citizens should have nothing to fear. This essay critically evaluates the \u27nothing to hide\u27 argument in light of surveillance in the digital age - both by governments and private actors. It will argue that people generally have things that they would rather keep private, and that breaches of this privacy can lead to \u27information-based harms\u27. Whilst UK and European surveillance law has developed safeguards against these, there remain significant risks in the form of foreign and private surveillance. Ultimately, it contributes to an ongoing discourse about the limits of individual privacy, and the role of the internet in democratic societies.