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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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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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Scooped by Julien Hering, PhD
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Sleep Oscillations in the Thalamocortical System Induce Long-Term Neuronal Plasticity

Sleep Oscillations in the Thalamocortical System Induce Long-Term Neuronal Plasticity | Neuroscience_topics | Scoop.it

Highlights

  • Slow-wave sleep induces long-term potentiation of evoked responses
  • In vitro, stimulation mimicking SWS replicated these results
  • Potentiation of responses was postsynaptic, Ca2+, AMPA, and NMDA dependent
  • The mechanism of potentiation was compatible with the classical LTP mechanism

Summary

Long-term plasticity contributes to memory formation and sleep plays a critical role in memory consolidation. However, it is unclear whether sleep slow oscillation by itself induces long-term plasticity that contributes to memory retention. Using in vivo prethalamic electrical stimulation at 1 Hz, which itself does not induce immediate potentiation of evoked responses, we investigated how the cortical evoked response was modulated by different states of vigilance. We found that somatosensory evoked potentials during wake were enhanced after a slow-wave sleep episode (with or without stimulation during sleep) as compared to a previous wake episode. In vitro, we determined that this enhancement has a postsynaptic mechanism that is calcium dependent, requires hyperpolarization periods (slow waves), and requires a coactivation of both AMPA and NMDA receptors. Our results suggest that long-term potentiation occurs during slow-wave sleep, supporting its contribution to memory.

Sylvain Chauvette, Josée Seigneur, Igor TimofeevNeuron, Volume 75, Issue 6, 1105-1113, 20 September 2012

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