The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

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.

Ensemble-specific deficit in neuronal intrinsic excitability in aged mice.

With the prevalence of age-related cognitive deficits on the rise, it is essential to identify cellular and circuit alterations that contribute to age-related memory impairment. Increased intrinsic neuronal excitability after learning is important for memory consolidation, and changes to this process could underlie memory impairment in old age. Some studies find age-related deficits in hippocampal neuronal excitability that correlate with memory impairment but others do not, possibly due to selective changes only in activated neural ensembles. Thus, we tagged CA1 neurons activated during learning and recorded their intrinsic excitability 5 hours or 7 days post-training. Adult mice exhibited increased neuronal excitability 5 hours after learning, specifically in ensemble (learning-activated) CA1 neurons. As expected, ensemble excitability returned to baseline 7 days post-training. In aged mice, there was no ensemble-specific excitability increase after learning, which was associated with impaired hippocampal memory performance. These results suggest that CA1 may be susceptible to age-related impairments in post-learning ensemble excitability and underscore the need to selectively measure ensemble-specific changes in the brain.

Hypoxia inhibits the cardiac I K1 current through SUMO targeting Kir2.1 activation by PIP2.

Cardiovascular diseases remain the leading cause of death worldwide. Most deaths are sudden and occur secondary to the occlusion of coronary arteries resulting in a rapid decrease in cellular oxygen levels. Acute hypoxia is proarrhythmic, leading to disordered electrical signals, conduction block, and uncoordinated beating of the myocardium. Although acute hypoxia is recognized to perturb the electrophysiology of heart muscle, the mechanistic basis for the effect has remained elusive, hampering the development of targeted therapeutic interventions. Here, we show that acute hypoxia activates the redox-sensitive SUMO pathway in cardiomyocytes, causing rapid inhibition of the inward-rectifying K+ channel, Kir2.1. We find that SUMOylation decreases the activation of Kir2.1 channels by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). These data provide a mechanistic basis for the proarrhythmic effects of acute hypoxia and offer a framework for understanding the central role of PIP2 in mediating the sequelae of hypoxia and SUMOylation in cardiovascular disease.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels.

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 (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.

Multifaceted Regulation of Potassium-Ion Channels by Graphene Quantum Dots.

Graphene quantum dots (GQDs) are emerging as a versatile nanomaterial with numerous proposed biomedical applications. Despite the explosion in potential applications, the molecular interactions between GQDs and complex biomolecular systems, including potassium-ion (K+) channels, remain largely unknown. Here, we use molecular dynamics (MD) simulations and electrophysiology to study the interactions between GQDs and three representative K+ channels, which participate in a variety of physiological processes and are closely related to many disease states. Using MD simulations, we observed that GQDs adopt distinct contact poses with each of the three structurally distinct K+ channels. Our electrophysiological characterization of the effects of GQDs on channel currents revealed that GQDs interact with the extracellular voltage-sensing domain (VSD) of a Kv1.2 channel, augmenting current by left-shifting the voltage dependence of channel activation. In contrast, GQDs form a "lid" cluster over the extracellular mouth of inward rectifier Kir3.2, blocking the channel pore and decreasing the current in a concentration-dependent manner. Meanwhile, GQDs accumulate on the extracellular "cap domain" of K2P2 channels and have no apparent impact on the K+ flux through the channel. These results reveal a surprising multifaceted regulation of K+ channels by GQDs, which might help de novo design of nanomaterial-based channel probe openers/inhibitors that can be used to further discern channel function.