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Type VI RTKs: PTK7/CCK4 in GtoPdb v.2025.3
Full text linkThe PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, hence acting as a pseudokinase. There is, however, evidence for a role in Wnt signalling [2], as well as an ability to form heteromers with other RTKs, such as VEGFR2 and ROR2
Type IX RTKs: MuSK in GtoPdb v.2025.3
Full text linkThe muscle-specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. agrin forms a complex with low-density lipoprotein receptor-related protein 4 to activate MuSK [5]. MuSK-mediated phosphorylation of downstream targets is involved in stabilised neuromuscular function. It is the target of pathogenic autoantibodies in myasthenia gravis, an autoimmune neuromuscular disease
Adenosine receptors in GtoPdb v.2025.4
Full text linkAdenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [114]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [155]. More recently, structures for the A2B receptor [58, 48] and the A3 receptor [279, 47] were elucidated. The A2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank (www.rcsb.org). istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson\u27s disease, while caffeine\u27s mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A1 and A3 receptors, have been explored chemically and structurally [88, 293]
Transient Receptor Potential channels (TRP) in GtoPdb v.2025.4
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 phosphoinositides 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 components of multimeric 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 noxious 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]
2A. Hepatocyte nuclear factor-4 receptors in GtoPdb v.2025.4
Full text linkThe nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [9, 3]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [80]. HNF4γ has yet to be paired with an endogenous ligand
Calcium activated chloride channel (CaCC) in GtoPdb v.2025.4
Full text linkChloride channels activated by intracellular Ca2+ (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [29]. 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 [31, 58, 22, 1, 52]. 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 [37, 18]. Alternative splicing regulates the voltage- and Ca2+-dependence of TMEM16A and such post-transcriptional process may be tissue-specific and contribute to functional diversity [23]. TMEM16A is a potential drug target for a variety of conditions spanning from respiratory to vascular (see "Comments" section for further detail)
3.6.5.2 Small monomeric GTPases in GtoPdb v.2025.4
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
Comparison of Multi-Organ Segmentation Tools for Whole-Body [18F]FDG-PET/CT Clinical Imaging
Full text linkTypically, delineation of volumes of interest (VOI) within clinical PET/CT imaging is performed manually. This is time consuming [1] and is highly vulnerable to inter/intra-operator variability resulting in differing delineations for the same patient [1]. Application of automated segmentation aims to address these issues in the VOI delineation process; increasing image throughput and reducing the current manual stochasticity involved. Moreover, automation in the segmentation process has the potential to galvanise downstream analyses, including network analysis [2]. Among the various automated multi-organ segmentation approaches, two methodologies Multiple-Organ Objective Segmentation (MOOSE) [3] and TotalSegmentator (TS) [4] have emerged as state-of-the-art (SOTA). Both methods leverage the nnU-Net framework as their underlying architecture. However, they differ in training dataset, nnU-Net configurations, and weights. Recently, Julie et al. [5] compared MOOSE and TotalSegmentator on a metastatic breast cancer dataset. However, gold-standard labels were not generated for this study and as a result, comparison against a verified gold-standard is not available, instead the authors focus on the degree of agreement and differences in feature values. Concurrent with Julie et al. [5], we look to compare MOOSE and TS, on a dataset of clinical stage IIB/III non-small cell lung carcinoma (NSCLC). We compare both methods versus gold-standard manual delineation and evaluate using current technical segmentation metrics alongside PET/CT outcome metrics (e.g. Hounsfield units (HU) and Standardised Uptake Values (SUV)) to assess if the automated methods introduce quantitative bias versus manual annotations.
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Hilbert-Huang Transform Analysis of Intradecadal Variations in the Length of Earth\u27s Day
Full text linkIntradecadal periods in the length of Earth\u27s day (∆LOD) reveal angular momentum exchanges as a result of processes in the Earth\u27s core. The properties of two previously identified intradecadal oscillations in the ∆LOD signal with periods of approximately 6 and 8.5 years, respectively, are investigated from 1962 to 2025, using the Hilbert-Huang transform method. Initially, angular momentum contributions from zonal tides and the Earth\u27s atmosphere are removed, before the application of Butterworth bandpass filters to isolate the oscillations. The two intradecadal oscillations are found to have periods of 5.8 ± 0.8 years and 9.1 ± 1.6 years, respectively. The six-year oscillation shows a decaying trend from 2010 onwards, associated with a shortening in the period of oscillation. The eight-year oscillation breaks down between 1995 and 2000, which may be linked with geomagnetic jerk activity
\u27Daughters of the North\u27: writing the biography of Jean Gordon and Mary, Queen of Scots
No full textThis article explores the creative processes of writing popular biography, from the first hand perspective. It examins their similarities to, and differences from, writing academic history or fiction. Henderson focusses on her recent book exploring the biographies, and connections, between Jean Gordon and Mary Queen of Scots, Daughters of the North. She explains how and why she made particular choices in writing about Scottish history, culture, music, literature and art