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3.6.5.2 Small monomeric GTPases in GtoPdb v.2025.3
Full text linkSmall G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases
Cannabinoid receptors in GtoPdb v.2025.1
Full text linkCannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [127]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [5].There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB1 and CB2 receptors [119]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB1/CB2 receptor agonist, and synthetic Δ9-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ9-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain
SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) in GtoPdb v.2025.1
Full text linkThe SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family) [1]
Galanin receptors in GtoPdb v.2025.1
Full text linkGalanin receptors (provisional nomenclature as recommended by NC-IUPHAR [57]) are activated by the endogenous peptides galanin and galanin-like peptide. Human galanin is a 30 amino-acid non-amidated peptide [52]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1-14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1-19 [21] and porcine galanin-5-29 [170]) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin [22, 170]) have been reported. More recently, the newly-identified peptide, spexin (SPX), has been reported to activate human GAL2 and GAL3 (but not GAL1) receptors in heterologous expression systems; and to alter GAL2/3 receptor-related behaviours in animals [89]
Transient Receptor Potential channels (TRP) in GtoPdb v.2025.1
Full text linkThe TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [177, 1080]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [734]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [404, 690, 1163, 258]. The established, or potential, involvement of TRP channels in disease [1134] is reviewed in [452, 689], [692] and [468], together with a special edition of Biochemica et Biophysica Acta on the subject [689]. Additional disease related reviews, for pain [637], stroke [1143], sensation and inflammation [994], itch [130], and airway disease [313, 1058], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [810]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1015, 693, 806]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel\u27s function is to act as a \u27hot\u27 or \u27cold\u27 sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [295]). TRPA1 activation of sensory neurons contribute to nociception [417, 895, 606]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [579, 60, 368, 581]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [428, 515, 1089, 1088]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [429, 213]. The electron cryo-EM structure of TRPA1 [745] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [286, 783, 18, 4, 94, 450, 744, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [770, 959, 1080]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [451]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [746, 18, 775, 825, 1129, 157, 730, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [350, 349]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [810, 623, 440, 102, 856, 192, 293]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [298, 71, 890, 1038, 1032, 154, 103, 565, 918, 412]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [230]. The structures of the apo and antagonist-bound states of TRPC1/TRPC4 heteromeric channels have been resolved by cryo-EM [1070]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1122, 727, 728, 1123, 543, 1176, 1117].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [350].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [277, 349, 746, 1159]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [401, 712]. TRPM3 (reviewed by [718]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [947]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [717, 946]. TRPM3 may contribute to the detection of noxious heat [1024]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [976] and cyclic ADPR (cADPR) [1126]. As for many ion channels, PI(4,5)P2 must also be present [1117]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [240]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [390, 1034]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1128]. TRPM2 is involved in warmth sensation [853], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1172]. Activation of TRPM2 in macrophages promotes atherosclerosis [1173, 1155]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1035]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1145, 1147]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1080]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [330]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [597]. Mutations are associated with conduction defects [407, 597, 884]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [999] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [541] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [517]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [247]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [173]. These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. PIP2 is required for TRPM6 and TRPM7 activation [815, 1085]. When either gene is deleted in mice, the result is embryonic lethality [416, 1073]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [483, 484]. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [626]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 471]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 179, 225] reviewed by [1017, 566, 461, 653]. Direct chemical agonists include menthol and icilin[1094]. Besides, linalool can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [68]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [516], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gated pathways [1119]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8\u27s temperature-sensitive function [195]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4α in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [560]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [12]. A cyclic peptide DeC‐1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [9]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and β-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [736]. TRPML (mucolipin) familyThe TRPML family [787, 1140, 780, 1092, 191] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [827]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [322, 147, 882]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [787, 694]). TRPP (polycystin) familyThe TRPP family (reviewed by [217, 215, 303, 1068, 377]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1080]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [348]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [910]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [1001]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6. TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [767, 887, 927]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [849]. The pharmacology of TRPV1 channels is discussed in detail in [332] and [1022]. TRPV2 is probably not a thermosensor in man [740], but has recently been implicated in innate immunity [551]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [205]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [127, 534]. TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [1064, 206, 655, 272]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1063]
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
Bradykinin receptors in GtoPdb v.2025.3
Full text linkBradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [94]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597
Chemokine receptors in GtoPdb v.2025.3
Full text linkChemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [460, 459, 32, 125]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33, 125]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [721] and aliases
Galanin receptors in GtoPdb v.2025.3
Full text linkGalanin receptors (provisional nomenclature as recommended by NC-IUPHAR [57]) are activated by the endogenous peptides galanin and galanin-like peptide. Human galanin is a 30 amino-acid non-amidated peptide [52]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1-14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1-19 [21] and porcine galanin-5-29 [171]) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin [22, 171]) have been reported. More recently, the newly-identified peptide, spexin (SPX), has been reported to activate human GAL2 and GAL3 (but not GAL1) receptors in heterologous expression systems; and to alter GAL2/3 receptor-related behaviours in animals [90]. Galanin and spexin neuropeptides are important regulators of energy homeostasis [58]
Metabotropic glutamate receptors in GtoPdb v.2025.3
Full text linkMetabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [354]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [141]. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [203, 278, 271, 406]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to other GPCRs, although the helices appear more compacted [89, 436, 63]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [220, 193], heterodimers [92, 163], and new insights into activation mechanisms [47, 48, 201]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [90]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [273, 443, 146, 286, 262, 221]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [141]). The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [29] and antagonised by (S)-hexylhomoibotenic acid [238]. Group-II mGlu receptors may be activated by LY389795 [272], LY379268 [272], eglumegad (also refered to as LY354470) [358, 437], DCG-IV and (2R,3R)-APDC [359], and antagonised by eGlu [172] and LY307452 [428, 106]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [131]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [187]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that recognise distinct sites primarily within the TM domain have been described. Negative allosteric modulators are listed separately. Positive allosteric modulators potentiate orthosteric agonist responses solely, or may also possess intrinsic agonist activity