Neuroscience_topics
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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Scooped by Julien Hering, PhD
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[Review] Opening paths to novel analgesics: the role of potassium channels in chronic pain

[Review] Opening paths to novel analgesics: the role of potassium channels in chronic pain | Neuroscience_topics | Scoop.it
Highlights- Potassium (K+) channels are crucial determinants of neuronal excitability.- Nerve injury or inflammation alters K+ channel activity in neurons of the pain pathway.- These changes can render neurons hyperexcitable and cause chronic pain.- Therapies targeting K+ channels may provide improved pain relief in these states. (...) - By Tsantoulas C & McMahon SB, Trends in Neurosciences, Volume 37, Issue 3, March 2014, Pages 146–158
Julien Hering, PhD's insight:

The exceptional abundance and breadth of function encountered in K+ channels has complicated efforts to untangle explicit roles in pain syndromes. Owing to advances in molecular, biochemical, electrophysiological, and genetic methods, however, we can now appreciate the involvement of specific subunits in maladaptive pain signaling after injury or inflammation. Nevertheless, there are many potential avenues of K+ involvement that have hardly been explored. It seems likely that unknown mutations in K+channel genes might contribute to inherited pain syndromes. There are many ‘silent’ K+ channel subunits for which we have little idea of whether and how they might affect pain processing. Auxiliary subunits can provide alternative substrates for pharmacological modulation; however, our understanding of these interactions in the PNS is also limited. In many chronic pain models an extensive dysregulation of several K+channels is seen, and it is unknown whether a common epigenetic control exists.

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Therapeutic potential of NaV1.1 activators

Highlights:- NaV1.1 is the major sodium current in specific inhibitory interneurons.- Interneuronal dysfunction is linked to epilepsies, schizophrenia, and AD.- NaV1.1 plays a modest role in excitatory neurons.- Selective NaV1.1 activators may hold great potential as a novel treatment paradigm.

By Jensen HS et al.,  Trends in Pharmacological Sciences, Volume 35, Issue 3, p113–118, March 2014

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Adenosine receptors as drug targets - what are the challenges?

[Review] Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.(...) - by Chen JF et al., Nature Reviews Drug Discovery, 12265-286 (April 2013)

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Ligand action on sodium, potassium, and calcium channels: role of permeant ions

Ligand action on sodium, potassium, and calcium channels: role of permeant ions | Neuroscience_topics | Scoop.it

Ion channels are targets for many naturally occurring toxins and small-molecule drugs. Despite great progress in the X-ray crystallography of ion channels, we still do not have a complete understanding of the atomistic mechanisms of channel modulation by ligands. In particular, the importance of the simultaneous interaction of permeant ions with the ligand and the channel protein has not been the focus of much attention. Considering these interactions often allows one to rationalize the highly diverse experimental data within the framework of relatively simple structural models. This has been illustrated in earlier studies on the action of local anesthetics, sodium channel activators, as well as blockers of potassium and calcium channels. Here, we discuss the available data with a view to understanding the use-, voltage-, and current carrying cation-dependence of the ligand action, paradoxes in structure–activity relationships, and effects of mutations in these ion channels. (...) - by Zhorov BS & Tikhonov DB, Trends in Pharmacological Sciences, In Press, Available online 1 February 2013

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Kv7 channels as targets for anti-epileptic and psychiatric drug-development

Kv7 channels as targets for anti-epileptic and psychiatric drug-development | Neuroscience_topics | Scoop.it
The Kv7 channels, a family of voltage-dependent K+ channels (Kv7.1–Kv7.5), have gained much attention in drug discovery especially because four members are genetically linked to diseases. For disorders of the CNS focus was originally on epilepsy and pain, but it is becoming increasingly evident that Kv7 channels can also be valid targets for psychiatric disorders, such as anxiety and mania. The common denominator is probably neuronal hyperexcitability in different brain areas, which can be successfully attenuated by pharmacological increment of Kv7 channel activity. This perspective attempts to review the current status and challenges for CNS drug discovery based on Kv7 channels as targets for neurological and psychiatric indications with special focus on selectivity and mode-of-actions. - by Grunnet M. et al., European Journal of Pharmacology, Volume 726, 5 March 2014, Pages 133–137
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Drug-evoked synaptic plasticity: beyond metaplasticity

Drug-evoked synaptic plasticity: beyond metaplasticity | Neuroscience_topics | Scoop.it
  • Addictive drugs alter synaptic plasticity in the VTA through a common mechanism.
  • Changes in the VTA are permissive for later mesocorticolimbic circuit remodeling.
  • Mesocorticolimbic circuit remodeling may underlie addiction-related behaviors.
  • Reversing drug-induced plasticity may ultimately suppress addiction-related behavior.

by Creed MC & Lüscher C, Current Opinion in Neurobiology, online 6 April 2013

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Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure–activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide. (...) - by Kenakin T. & Christopoulos A.Nature Reviews Drug Discovery 12205-216 (March 2013)

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