Search

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is 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 almost 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/10.1111/bph.16178. 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-2023, and supersedes data presented in the 2021/22, 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.

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+—prolyl hydroxylase domain enzymes (PHDs)—NF-κB—interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease. Lysosomes are best known for their roles in inflammatory responses via autophagy. Here, Xing et al., find that lysosomes regulate macrophage inflammatory responses by finely controlling interleukin-1β production, altering lysosomal Fe2+ release through the TRPML1 channel. [ABSTRACT FROM AUTHOR]

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well as those in the degradative pathway (early endosomes, macropinosomes, phagosomes, autophagosomes, late endosomes, and lysosomes). These endomembrane organelles/vesicles work together to synthesize, modify, package, transport, and degrade proteins, carbohydrates, and lipids, regulating the balance between cellular anabolism and catabolism. Large ion concentration gradients exist across endomembranes: Ca2+ gradients for most endomembrane organelles and H+ gradients for the acidic compartments. Ion (Na+, K+, H+, Ca2+, and Cl−) channels on the organellar membranes control ion flux in response to cellular cues, allowing rapid informational exchange between the cytosol and organelle lumen. Recent advances in organelle proteomics, organellar electrophysiology, and luminal and juxtaorganellar ion imaging have led to molecular identification and functional characterization of about two dozen endomembrane ion channels. For example, whereas IP3R1–3 channels mediate Ca2+ release from the ER in response to neurotransmitter and hormone stimulation, TRPML1–3 and TMEM175 channels mediate lysosomal Ca2+ and H+ release, respectively, in response to nutritional and trafficking cues. This review aims to summarize the current understanding of these endomembrane channels, with a focus on their subcellular localizations, ion permeation properties, gating mechanisms, cell biological functions, and disease relevance. [ABSTRACT FROM AUTHOR]

Lysosome acidification is a dynamic equilibrium of H+ influx and efflux across the membrane, which is crucial for cell physiology. The vacuolar H+ ATPase (V‐ATPase) is responsible for the H+ influx or refilling of lysosomes. TMEM175 was identified as a novel H+ permeable channel on lysosomal membranes, and it plays a critical role in lysosome acidification. However, how TMEM175 participates in lysosomal acidification remains unknown. Here, we present evidence that TMEM175 regulates lysosomal H+ influx and efflux in enlarged lysosomes isolated from COS1 treated with vacuolin‐1. By utilizing the whole‐endolysosome patch‐clamp recording technique, a series of integrated lysosomal H+ influx and efflux signals in a ten‐of‐second time scale under the physiological pH gradient (luminal pH 4.60, and cytosolic pH 7.20) was recorded from this in vitro system. Lysosomal H+ fluxes constitute both the lysosomal H+ refilling and releasing, and they are asymmetrical processes with distinct featured kinetics for each of the H+ fluxes. Lysosomal H+ fluxes are entirely abolished when TMEM175 losses of function in the F39V mutant and is blocked by the antagonist (2‐GBI). Meanwhile, lysosomal H+ fluxes are modulated by the pH‐buffering capacity of the lumen and the lysosomal glycosylated membrane proteins, lysosome‐associated membrane protein 1 (LAMP1). We propose that the TMEM175‐mediated lysosomal H+ fluxes model would provide novel thoughts for studying the pathology of Parkinson's disease and lysosome storage disorders. [ABSTRACT FROM AUTHOR]

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe 2+ -prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe 2+ , which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage-sensing site at D131 and can be deactivated in a frequency-dependent manner by membrane depolarization. This voltage-dependent D2R inhibition of DA release is mediated via the facilitation of voltage-gated Ca 2+ channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage-sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA-dependent functions in vivo., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo , LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.