Utilization of iPSC-derived human neurons for high-throughput drug-induced peripheral neuropathy screening.

As the number of cancer survivors continues to grow, awareness of long-term toxicities and impact on quality of life after chemotherapy treatment in cancer survivors has intensified. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of modern chemotherapy. Animal models are used to study peripheral neuropathy and predict human risk; however, such models are labor-intensive and limited translatability between species has become a major challenge.

5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner.

The common neurotransmitter serotonin controls different aspects of early neuronal differentiation, although the underlying mechanisms are poorly understood. Here we report that activation of the serotonin 5-HT(7) receptor promotes synaptogenesis and enhances synaptic activity in hippocampal neurons at early postnatal stages. An analysis of Gα(12)-deficient mice reveals a critical role of G(12)-protein for 5-HT(7) receptor-mediated effects in neurons.

Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models.

Introduction: The field of cardiac safety pharmacology has been experiencing exciting changes over the recent years. Drug induced arrhythmia of the torsade des pointes types has been the reason for the denial of approval of novel drug candidates. The aim of cardiac safety pharmacology is to detect undesirable pharmacodynamic drug effects within and above the therapeutic range.

Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established.

Characterization of Na+-activated K+ currents in larval lamprey spinal cord neurons.

Potassium channels play an important role in controlling neuronal firing and synaptic interactions. Na(+)-activated K(+) (K(Na)) channels have been shown to exist in neurons in different regions of the CNS, but their physiological function has been difficult to assess. In this study, we have examined if neurons in the spinal cord possess K(Na) currents.

mGluR1, but not mGluR5, mediates depolarization of spinal cord neurons by blocking a leak current.

The modulation of neuronal excitability by group I metabotropic glutamate receptors (mGluRs) was studied in isolated lamprey spinal cord. At resting potential, application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) slightly depolarized the cells. However, at depolarized membrane potentials, this agonist induced repetitive firing.

Metabotropic glutamate receptors provide intrinsic modulation of the lamprey locomotor network.

Spinal networks generate the motor pattern underlying locomotion. These are subject to modulatory systems that influence their operation and thereby result in a flexible network organization. In this review, we have summarized the mechanisms by which the different metabotropic glutamate receptor subtypes fine-tune the cellular and synaptic properties and thus underlie intrinsic modulation of the activity of the locomotor network in the lamprey.

Signaling mechanisms of metabotropic glutamate receptor 5 subtype and its endogenous role in a locomotor network.

Metabotropic glutamate receptors (mGluRs) act as modulators in the CNS of vertebrates, but their role in motor pattern generation in particular is primarily unknown. The intracellular signaling mechanisms of the group I mGluRs (mGluR1 and mGluR5), and their endogenous role in regulating locomotor pattern generation have been investigated in the spinal cord of the lamprey. Application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) produced oscillations of the intracellular Ca2+ concentration ([Ca2+]i) in neurons.