The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Transient receptor potential canonical (TRPC) channels are Ca2؉ -permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca 2؉ rise in response to stimulation of mouse TRPC4 by -opioid receptors. ML204 inhibited TRPC4-mediated intracellular Ca 2؉ rise with an IC 50 value of 0.96 M and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In wholecell patch clamp recordings, ML204 blocked TRPC4 currents activated through either -opioid receptor stimulation or intracellular dialysis of guanosine 5-3-O-(thio)triphosphate (GTP␥S), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10 -20 M ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTP␥S, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.
Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors, but rodent models of pain-related OA have concentrated on allodynia rather than ongoing pain, and on OA generated in non-nociceptive Aβ fibers rather than C-fiber nociceptors. Little is known about how ongoing pain or nociceptor OA is generated. To define neurophysiological alterations underlying nociceptor OA, we have used isolated dorsal root ganglion neurons that continue to generate OA after removal from animals displaying ongoing pain. We subclassify OA as either spontaneous activity generated solely by alterations intrinsic to the active neuron or as extrinsically driven OA. Both types of OA were implicated previously in nociceptors in vivo and after isolation following spinal cord injury, which produces chronic ongoing pain. Using novel automated algorithms to analyze irregular changes in membrane potential, we have found, in a distinctive, nonaccommodating type of probable nociceptor, induction by spinal cord injury of 3 alterations that promote OA: (1) prolonged depolarization of resting membrane potential, (2) a hyperpolarizing shift in the voltage threshold for action potential generation, and (3) an increase in the incidence of large depolarizing spontaneous fluctuations (DSFs). Can DSFs also be enhanced acutely to promote OA in neurons from uninjured animals? A low dose of serotonin failed to change resting membrane potential but lowered action potential threshold. When combined with artificial depolarization to model inflammation, serotonin also strongly potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA that may promote ongoing pain in chronic and acute conditions.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Transient receptor potential canonical (TRPC) channels constitute a group of receptor-operated calcium-permeable nonselective cation channels of the TRP superfamily. The seven mammalian TRPC members, which can be further divided into four subgroups (TRPC1, TRPC2, TRPC4/5, and TRPC3/6/7) based on their amino acid sequences and functional similarities, contribute to a broad spectrum of cellular functions and physiological roles. Studies have revealed complexity of their regulation involving several components of the phospholipase C pathway, G i and G o proteins, and internal Ca 2+ stores. Recent advances in cryogenic electron microscopy have provided several high-resolution structures of TRPC channels. Growing evidence demonstrates the involvement of TRPC channels in diseases, particularly the link between genetic mutations of TRPC6 and familial
Stem cell-derived motor neurons (MNs) are increasingly utilized for modeling disease in vitro and for developing cellular replacement strategies for spinal cord injury and diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Human embryonic stem cell (hESC) differentiation into MNs, which involves retinoic acid (RA) and activation of the sonic hedgehog (SHH) pathway is inefficient and requires up to 60 days to develop MNs with electrophysiological properties. This prolonged differentiation process has hampered the use of hESCs, in particular for high-throughput screening. We evaluated the MN gene expression profile of RA/SHH-differentiated hESCs to identify rate-limiting factors involved in MN development. Based on this analysis, we developed an adenoviral gene delivery system encoding for MN inducing transcription factors: neurogenin 2 (Ngn2), islet-1 (Isl-1), and LIM/homeobox protein 3 (Lhx3). Strikingly, delivery of these factors induced functional MNs with mature electrophysiological properties, 11-days after gene delivery, with >60-70% efficiency from hESCs and human induced pluripotent stem cells (hiPSCs). This directed programming approach significantly reduces the time required to generate electrophysiologically-active MNs by approximately 30 days in comparison to conventional differentiation techniques. Our results further exemplify the potential to use transcriptional coding for rapid and efficient production of defined cell types from hESCs and hiPSCs.
Transient receptor potential channels are involved in sensing chemical and physical changes inside and outside of cells. TRPV3 is highly expressed in skin keratinocytes, where it forms a nonselective cation channel activated by hot temperatures in the innocuous and noxious range. The channel has also been implicated in flavor sensation in oral and nasal cavities as well as being a molecular target of some allergens and skin sensitizers. TRPV3 is unique in that its activity is sensitized upon repetitive stimulations. -mediated inhibition and greatly facilitated the activation of TRPV3. We conclude that Ca 2؉ inhibits TRPV3 from both the extracellular and intracellular sides. The inhibition is sequentially reduced, appearing as sensitization to repetitive stimulations. Members of the transient receptor potential (TRP)4 superfamily of cation channels have been recognized to play important roles in sensing various environmental changes inside and outside of cells as well as the whole organisms (1). In mammals, temperature sensing is thought to be accomplished through concerted actions of a minimum of six TRP channels, i.e. TRPA1, -M8, -V4, -V3, -V1, and -V2, each covering a defined temperature range from below 17°C to above 52°C (2, 3). However, the debate remains whether some of these channels, e.g. TRPA1, are really temperature-sensitive (4). In addition, TRPM2, -M4, and -M5 have shown temperature sensing in the presence of second messenger cofactors, such as ADP-ribose and Ca 2ϩ (5, 6). Although some of the thermosensitive TRP channels are clearly expressed and functional in sensory neurons, indicative of their actions in primary afferents, others have been localized in the non-nervous tissues, for example, TRPV3 and -V4 are expressed in skin keratinocytes (7,8) and TRPV3 is, in addition, expressed in the epithelium of tongue and nose (9). The TRPV3 null mice showed some deficits in sensing hot temperatures in the innocuous and noxious range but no other obvious sensory impairment (10). On the other hand, constitutively active mutations of TRPV3 have been linked to hair loss and atopic dermatitis-like skin lesions in rodents (11,12).In addition to temperature, the thermosensitive TRP channels are activated by a large number of structurally unrelated chemical ligands from exogenous as well as endogenous sources (13). This polymodal nature has become a common feature of the TRP channel family, implicating that multiple mechanisms and external stimuli may be involved in the activation and regulation of these channels. TRPV3 was first shown to be activated by 2-aminoethoxydiphenyl borate (2APB), a synthetic compound known to inhibit inositol 1,4,5-trisphosphate receptors and store-operated channels as well as many TRP channels (14, 15). It was soon discovered that a number of natural anti-irritants and flavor enhancers such as camphor, carvacrol, thymol, and eugenol, also use TRPV3 as one of their targets (9, 10). More importantly, cell signaling events leading to the activation of phospholipase C, phosphorylation by...
Transient receptor potential A1 (TRPA1) forms non-selective cation channels implicated in acute inflammatory pain and nociception. The mechanism of ligand activation of TRPA1 may involve either covalent modification of cysteine residues or conventional reversible ligand-receptor interactions. For certain electrophilic prostaglandins, covalent modification has been considered as the main mechanism involved in their stimulatory effect on TRPA1. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins, we examined several non-electrophilic NSAIDs on TRPA1 activation using electrophysiological techniques and intracellular Ca 2+ measurements and found that a selected group of NSAIDs can act as TRPA1 agonists. Extracellularly applied flufenamic, niflumic, and mefenamic acid, as well as flurbiprofen, ketoprofen, diclofenac, and indomethacin, rapidly activated rat TRPA1 expressed in Xenopus oocytes and human TRPA1 endogenously expressed in WI-38 fibroblasts. Similarly, the NSAID ligands activated human TRPA1 inducibly expressed in HEK293 cells, but the responses were absent in uninduced and parental HEK293 cells. The response to fenamate agonists was blocked by TRPA1 antagonists, AP-18, HC-030031, and ruthenium red. At subsaturating concentrations, the fenamate NSAIDs also potentiate the activation of TRPA1 by allyl isothiocyanate, cinnamaldehyde, and cold, demonstrating positive synergistic interactions with other well-characterized TRPA1 activators. Importantly, among several thermosensitive TRP channels, the stimulatory effect is specific to TRPA1 because flufenamic acid inhibited TRPV1, TRPV3 and TRPM8. We conclude that fenamate NSAIDs are novel class of potent and reversible direct agonists of TRPA1. This selective group of TRPA1-stimulating NSAIDs should provide a structural basis for developing novel ligands that noncovalently interact with TRPA1 channels.
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