IUPHAR/BPS Guide to Pharmacology CITE
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RAS subfamily in GtoPdb v.2025.3
Full text linkThe RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules of 21 kd. They act as an on/off switch linking receptor and non-receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.The RAS proto-oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP-hydrolysing ability of the proteins causing constitutive activation [38], which leads to increased cell proliferation and decreased apoptosis [49]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [2]
Opioid receptors in GtoPdb v.2025.1
Full text linkOpioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [126, 103, 94]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered \u27opioid-related\u27 rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [310], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone. The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol, in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin, are in clinical use for itch
Pattern recognition receptors in GtoPdb v.2025.1
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
Coronavirus (CoV) proteins in GtoPdb v.2025.1
Full text linkCoronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (WHO Technical Guidance 2020)
Calcium-sensing receptor in GtoPdb v.2025.3
Full text linkThe calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [49] and subsequently updated [81]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [82]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 115], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [36, 49, 65, 113, 114]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [155, 57]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [18] or decreased extracellular ionic strength [114] while sensitivity is decreased by pathophysiological phosphate concentrations [20]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS
Prostanoid receptors in GtoPdb v.2025.3
Full text linkProstanoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [709]) are activated by the endogenous ligands prostaglandins PGD2, PGE1, PGE2 , PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Differences and similarities between human and rodent prostanoid receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [457]. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies
Epithelial sodium channel (ENaC) in GtoPdb v.2025.3
Full text linkOverviewThe 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, 49, 15, 24, 23]. 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 [43]. 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 [44]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [44, 33].The genetics of the hereditary systemic pseudohypoaldosteronism type-I revealed that the activity of ENaC is dependent on three subunits encoded by three genes [24, 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, 27]. The first 3D structure of human ENaC was determined by single-particle cryo-electron microscopy at a resolution of 3.7 Å [39]. A recent study improved the resolution to 3 Å [40]. 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 [30]. 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 [17]. 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 [17]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on the non-cilial cell surface [17]. 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 [49]. 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 [49]. Thus, ENaC function regulates the volume of fluid lining epithelia essential for mucociliary clearance of respiratory airways, transport of germ cells, fertilization, implantation, and cell migration [38, 17, 24]. Genes and PhylogenyIn the human genome, there are four homologous genes (SCNN1A, SCNN1B, SCNN1D, and SCNN1G) that encode four proteins, α-, β-, γ-, and δ-ENaC that may be involved in the assembly of ENaC [11, 35, 48, 54]. These four subunits share 23-34% sequence identity and <20% identity with ASIC subunits [24]. The genes coding for all four ENaC subunits are present in all bony vertebrates with the exception of ray-finned fish genomes that have lost all ENaC genes. The mouse genome has lost the gene SCNN1D that codes for δ-ENaC [19, 24, 24]. The α-, β-, and γ-ENaC genes are also present in jawless vertebrates (e.g., lampreys) and cartilaginous fishes (e.g., sharks) [24]. Examination of the methylation patterns of the 5\u27-flanking region of SCNN1A, SCNN1B, and SCNN1G genes in human cells showed an inverse correlation between gene expression and DNA methylation, suggesting epigenetic transcriptional control of ENaC genes [42]. Channel biogenesis, assembly and functionThe expression of ENaC subunits is regulated primarily by aldosterone and many additional extracellular and intracellular factors [44, 32, 41]. Most of the studies indicate that the expression of the three subunits is not coordinated [9]. However, the transport of the subunits to the membrane is dependent on three intact subunits. Even a missense mutation in one subunit reduces the concentration of assembled channels on the cell surface [16]. ENaC is a constitutively active channel, i.e., the flow of Na+ ions is not dependent on an activating factor. Hence, heterologous cells expressing ENaC (e.g., Xenopus oocytes), must be maintained in a solution that contains amiloride to keep ENaC inhibited. To measure ENaC activity, the bath solution is switched to a solution without amiloride. ENaC has two major states: 1) Open, and 2) Closed. The probability of ENaC being in the open state is called ENaC open probability (Po). ENaC activity is regulated by a diverse array of factors that exert their effects by modifying, directly or indirectly, two major parameters: 1) The density of ENaC in the membrane; and 2) The channel open probability [28, 30]. The Po of ENaC is greatly decreased by external Na+ and this response is called Na+ self-inhibition [50, 4, 26].An important aspect of ENaC regulation is that the α and the γ subunits have conserved serine protease cleavage sites in the extracellular segment [24]. Cleavage of these subunits by proteases such as furin and plasmin leads to the activation of ENaC [45, 31, 1].Diseases associated with ENaC mutationsMutations in any of the three genes (SCNN1A, SCNN1B, and SCNN1G) may cause partial or complete loss of ENaC activity, depending on the mutation [12, 21]. Such loss-of-function mutations are associated with a syndrome named "systemic" or "multi-system" autosomal recessive pseudohypoaldosteronism type I (PHA1B) [20, 12, 24, 17, 56, 47]. So far, no mutation has been found in the SCNN1D gene that causes PHA. PHA patients suffer from severe salt loss from all aldosterone target organs expressing ENaC, including kidney, sweat and salivary glands and respiratory tract. During infancy and early childhood, the severe electrolyte disturbances, dehydration and acidosis may require recurrent hospitalizations. The severity and frequency of salt-wasting episodes improve with age [22]. PHA1B is also associated with a dysfunctional female reproductive system [17, 6]. The carboxy-terminal of ENaC includes a short consensus sequence called the PY motif. Mutations in this motif in SCNN1B and SCNN1G are associated with Liddle syndrome, which is characterized by early-onset hypertension [5, 51]. The PY motif is recognized by Nedd4-2 that is a ubiquitin ligase. Thus, mutations in the PY motif reduce ubiquitylation of ENaC leading to the accumulation of ENaC in the membrane, consequently enhance the activity of ENaC [46].ENaC expression in tumorsThe observation that [Na+] is higher in many cancerous cells as compared to non-cancerous cells has led to the suggestion that enhanced expression of ENaC may be responsible for increased metastasis [34]. However, analysis of RNA sequencing data of ENaC-encoding genes, and clinical data of cervical cancer patients from The Cancer Genome Atlas showed a negative correlation with histologic grades of tumor [52]. Similarly, studies on breast cancer cells that altered α-ENaC levels by over-expression or siRNA-mediated knockdown showed that increased α-ENaC expression was associated with decreased breast cancer cell proliferation [55]. In contrast, analysis of RNA sequencing data from The Cancer Genome Atlas showed that high expression of SCNN1A was correlated with poor prognosis in patients with ovarian cancer [36]. These findings indicate that the association of ENaC levels with tumorigenesis varies depending on the tissue.COVID-19The surface of SARS-CoV-2 virions that cause COVID-19 is covered by many glycosylated S (spike) proteins. These S proteins bind to the membrane-bound angiotensin-converting enzyme 2 (ACE2) as a first step in the entry of the virion into the host cell. Viral entry into the cell is dependent on the cleavage of the S protein (at Arg-667/Ser-668) by a serine-protease. Anand et al. showed that this cleavage site has a sequence motif that is homologous to the furin cleavage site in α-ENaC [2]. A comprehensive review on the pathological consequences of COVID-19 suggests a role for ENaC in the early phases of COVID-19 infection in the respiratory tract epithelia [18]
SLC25 family of mitochondrial transporters in GtoPdb v.2025.3
Full text linkMitochondrial carriers are nuclear-encoded proteins, which translocate solutes across the inner mitochondrial membrane. Mitochondrial carriers are functional as monomers and have six TM alpha-helices and the termini in the mitochondrial intermembrane space
SLC28 and SLC29 families of nucleoside transporters in GtoPdb v.2025.3
Full text linkNucleoside transporters are divided into two families, the sodium-dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations [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]