First Evidence of Kv3.1b Potassium Channel Subtype Expression during Neuronal Serotonergic 1C11 Cell Line Development

Abstract

Kv3.1 channel is abundantly expressed in neurons and its dysfunction causes sleep loss, neurodegenerative diseases and depression. Fluoxetine, a serotonin selective reuptake inhibitor commonly used to treat depression, acts also on Kv3.1. To define the relationship between Kv3.1 and serotonin receptors (SR) pharmacological modulation, we showed that 1C11, a serotonergic cell line, expresses different voltage gated potassium (VGK) channels subtypes in the presence (differentiated cells (1C11D)) or absence (not differentiated cells (1C11ND)) of induction. Only Kv1.2 and Kv3.1 transcripts increase even if the level of Kv3.1b transcripts is highest in 1C11D and, after fluoxetine, in 1C11ND but decreases in 1C11D. The Kv3.1 channel protein is expressed in 1C11ND and 1C11D but is enhanced by fluoxetine only in 1C11D. Whole cell measurements confirm that 1C11 cells express (VGK) currents, increasing sequentially as a function of cell development. Moreover, SR 5HT1b is highly expressed in 1C11D but fluoxetine increases the level of transcript in 1C11ND and significantly decreases it in 1C11D. Serotonin dosage shows that fluoxetine at 10 nM blocks serotonin reuptake in 1C11ND but slows down its release when cells are differentiated through a decrease of 5HT1b receptors density. We provide the first experimental evidence that 1C11 expresses Kv3.1b, which confirms its major role during differentiation. Cells respond to the fluoxetine effect by upregulating Kv3.1b expression. On the other hand, the possible relationship between the fluoxetine effect on the kinetics of 5HT1b differentiation and Kv3.1bexpression, would suggest the Kv3.1b channel as a target of an antidepressant drug as well as it was suggested for 5HT1b.

Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom

“…It is evident that Kv3.1 is functionally relevant in adult Neural Progenitor Cell (NPC) expansion and neuronal lineage commitment [9,10] and we have also confirmed its role during 1C11 cell line differentiation, which is used as an in vitro model for serotonergic release [11]. The pharmacological and genetic disruption of Kv3 currents leads to impaired fast spiking in inhibitory neurons and increased seizure susceptibility which explains why Kv3.1 channel loss of function causes many physiological disorders such as ataxia, myoclonus, tremor, hyperactivity and reduction in sleep time [7,8], in addition to alterations in synaptic transmission at the parallel fibre-Purkinje cell synapses [12].…”

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression

“…Mice with a reduced level of Kv3.1 presented vulnerability to depressive behavior, whereas up-regulation of Kv3.1 or acute activation of Kv3.1 induced resilience to depression 56 . A commonly used antidepressant drug, Fluoxetine, acts on Kv3 channels to affect Kv3.1b expression and serotonin secretion in a serotonergic cell line 57 , and another similar drug Vortioxetine inhibits delayed-rectifier K+ current caused by Kv3 channels activity in pituitary GH3 cells 58 . KCNJ11 is highly expressed in the cerebellum (the second highest besides muscle) and encodes an integral membrane protein that is the key to an inward-rectifier potassium channel, the Kir6.2 subunit of ATP-sensitive potassium channel.…”

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

“…Mice with a reduced level of Kv3.1 presented vulnerability to depressive behavior, whereas up-regulation of Kv3.1 or acute activation of Kv3.1 induced resilience to depression 46 . A commonly used antidepressant drug, Fluoxetine, acts on Kv3 channels to affect Kv3.1b expression and serotonin secretion in a serotonergic cell line 47 , and another similar drug Vortioxetine inhibits delayed-rectifier K+ current caused by Kv3 channels activity in pituitary GH3 cells 48 . KCNJ11 is highly expressed in the cerebellum (the second highest besides muscle) and encodes an integral membrane protein that is the key to an inward-rectifier potassium channel, the Kir6.2 subunit of ATP-sensitive potassium channel.…”