The Concise Guide to PHARMACOLOGY 2023/24: Ion channels

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 180(S2)

Published: Oct. 1, 2023

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. provides concise overviews, mostly tabular format, key properties approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There an emphasis on selective pharmacology (where available), plus links open access knowledgebase source targets their ligands (https://www.guidetopharmacology.org/), which more detailed views target ligand properties. Although constitutes almost 500 pages, material presented substantially reduced compared information website. It a permanent, citable, point-in-time record that will survive database updates. full contents section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178. Ion channels are one six major pharmacological into divided, others being: G protein-coupled receptors, nuclear hormone catalytic enzymes transporters. These nomenclature guidance summary best available tools, alongside references suggestions for further reading. landscape format designed facilitate comparison related from contemporary mid-2023, supersedes data 2021/22, 2019/20, 2017/18, 2015/16 2013/14 Guides previous Receptors Channels. produced close conjunction Nomenclature Standards Committee International Union Basic Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification human where appropriate.

Language: Английский

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Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons

Cell Reports, Journal Year: 2020, Volume and Issue: 32(11), P. 108156 - 108156

Published: Sept. 1, 2020

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of synaptic inputs onto SNc from genetically defined populations dorsal striatum (striosome and matrix) external globus pallidus (GPe; parvalbumin- Lhx6-positive), examined their contribution pause-rebound firing. Activation striosome projections, which target "dendron bouquets" the pars reticulata (SNr), consistently quiets relief inhibition triggers activity. Striosomal postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens impact SNr dendrite synapses on somatic excitability enables rebounding. By contrast, GPe projections activate GABA-A receptors soma proximal dendrites but do not result Lastly, optical mapping shows selectively inhibits ventral population neurons, are intrinsically capable Therefore, we define distinct striatonigral circuit for generating dopamine rebound.

Language: Английский

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Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Nov. 8, 2019

Degeneration of dopaminergic neurons in the substantia nigra causes motor symptoms Parkinson's disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators nigral neuronal viability. transcripts were more abundant than other voltage-gated Ca2+ mouse upregulated during aging. Plasmalemmal protein was higher ventral tegmental area, which do not degenerate knockout reduced activity-associated somatic signals Ca2+-dependent after-hyperpolarizations, afforded full protection from degeneration vivo a neurotoxin model. deficiency for NCS-1, Ca2+-binding implicated neuroprotection. Conversely, NCS-1 exacerbated downregulated Cav2.3. Moreover, levels human iPSC-model familial Parkinson's. Thus, may constitute potential therapeutic targets combatting

Language: Английский

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Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Journal of Neurophysiology, Journal Year: 2021, Volume and Issue: 125(5), P. 1899 - 1919

Published: April 7, 2021

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within United States, rate from abuse since early 1990s has grown disproportionally, prompting classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular systems-level mechanisms opioid-related death. However, factors such individual vulnerability, neuromodulatory compensation, redundancy effects across central peripheral nervous systems created barrier concise, integrative view OIRD. review, bring together multiple perspectives in field OIRD create an overarching viewpoint what know, where essential topic research going forward into future.

Language: Английский

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The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium

Science Advances, Journal Year: 2020, Volume and Issue: 6(17)

Published: April 24, 2020

The sodium leak channel (NALCN) is essential for survival in mammals: NALCN mutations are life-threatening humans and knockout lethal mice. However, the basic functional pharmacological properties of have remained elusive. Here, we found that robust function heterologous systems requires co-expression UNC79, UNC80, FAM155A. resulting complex constitutively active conducts monovalent cations but blocked by physiological concentrations extracellular divalent cations. Our data support notion directly responsible increased excitability observed a variety neurons reduced Ca2+. Despite smaller number voltage-sensing residues NALCN, constitutive activity modulated voltage, suggesting domains can give rise to broader range gating phenotypes than previously anticipated. work points toward formerly unknown contributions neuronal opens avenues targeting.

Language: Английский

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New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 399 - 472

Published: Aug. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Language: Английский

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Structure of the human sodium leak channel NALCN

Nature, Journal Year: 2020, Volume and Issue: 587(7833), P. 313 - 318

Published: July 22, 2020

Language: Английский

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Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Sept. 1, 2020

Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell perforated-patch recordings test for on main neuron axons branching processes within adult mice. Application depolarized axons, also decreased amplitude axonal spikes, limited propagation reduced release. The mechanism inhibition involved sodium channel inactivation shunting. Lastly, show positive allosteric modulator diazepam enhanced currents inhibited likely acts by reducing excitation from cholinergic interneurons. Thus, reveal mechanisms receptor modulation release provide new insights into actions benzodiazepines striatum.

Language: Английский

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Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

iScience, Journal Year: 2020, Volume and Issue: 23(10), P. 101552 - 101552

Published: Sept. 11, 2020

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play role in disease pathogenesis. However, no unbiased, large-scale genomic study has been performed date. Analysis 290 whole exome-sequenced probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment rare, damaging variants GABA receptor-binding genes cases. Mice engineered with TN-associated de novo mutation (p.Cys188Trp) the GABAA receptor Cl- channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia behavior. Other probands harbored rare Na+ Ca+ channels, significant variant burden α-1H voltage-gated Ca2+ Cav3.2 (CACNA1H). These results provide exome-level insight into implicate genetically encoded impairment signaling neuronal ion transport

Language: Английский

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Activity-dependent somatodendritic dopamine release in the substantia nigra autoinhibits the releasing neuron

Cell Reports, Journal Year: 2021, Volume and Issue: 35(1), P. 108951 - 108951

Published: April 1, 2021

Somatodendritic dopamine (DA) release from midbrain DA neurons activates D2 autoreceptors on these cells to regulate their activity. However, the source of autoregulatory remains controversial. Here, we test hypothesis that a given neuron in substantia nigra pars compacta (SNc) are activated primarily by released same cell, rather than its neighbors. Voltage-clamp recording allows monitoring evoked D2-receptor-mediated inhibitory currents (D2ICs) SNc as an index release. Single-cell application antibodies Na+ channels via pipette decreases spontaneous activity recorded and attenuates D2ICs; SNAP-25, soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, also decrease D2IC amplitude. Evoked D2ICs nearly abolished light chain botulinum neurotoxin A, which cleaves whereas synaptically GABAB-receptor-mediated unaffected. Thus, somatodendritic autoinhibits releases it.

Language: Английский

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