A molecular rheostat: Kv2.1 currents maintain or suppress repetitive firing in motoneurons

Abstract

Key points Kv2 currents maintain and regulate motoneuron (MN) repetitive firing properties. Kv2.1 channel clustering properties are dynamic and respond to both high and low activity conditions. The enzyme calcineurin regulates Kv2.1 ion channel declustering. In patholophysiological conditions of high activity, Kv2.1 channels homeostatically reduce MN repetitive firing. Modulation of Kv2.1 channel kinetics and clustering allows these channels to act in a variable way across a spectrum of MN activity states. Abstract Kv2.1 channels are widely expressed in the central nervous system, including in spinal motoneurons (MNs) where they aggregate as distinct membrane clusters associated with highly regulated signalling ensembles at specific postsynaptic sites. Multiple roles for Kv2 channels have been proposed but the physiological role of Kv2.1 ion channels in mammalian spinal MNs is unknown. To determine the contribution of Kv2.1 channels to rat α‐motoneuron activity, the Kv2 inhibitor stromatoxin was used to block Kv2 currents in whole‐cell current clamp electrophysiological recordings in rat lumbar MNs. The results indicate that Kv2 currents permit shorter interspike intervals and higher repetitive firing rates, possibly by relieving Na+ channel inactivation, and thus contribute to maintenance of repetitive firing properties. We also demonstrate that Kv2.1 clustering properties in motoneurons are dynamic and respond to both high and low activity conditions. Furthermore, we show that the enzyme calcineurin regulates Kv2.1 ion channel clustering status. Finally, in a high activity state, Kv2.1 channels homeostatically reduce motoneuron repetitive firing. These results suggest that the activity‐dependent regulation of Kv2.1 channel kinetics allows these channels to modulate repetitive firing properties across a spectrum of motoneuron activity states.

Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons

“…One stimulus that results in dephosphorylation of Kv2.1 and dispersal of Kv2.1 clusters in CHNs is acute elevation in intracellular Ca 2+ in response to treatment with the excitatory neurotransmitter glutamate (Misonou et al, 2004; Misonou et al, 2006). In contrast, suppression of neuronal activity with tetrodotoxin (TTX) causes an increase in Kv2.1 phosphorylation and clustering (Cerda and Trimmer, 2011; Romer et al, 2019). We found that glutamate stimulation of CHNs not only reduced Kv2.1 clustering, but also significantly decreased the colocalization between Cav1.2 and RyRs, decreased the size of somatic RyR clusters, and increased the distance between somatic Cav1.2 clusters (Figure 1J–N).…”

NeurodegenERation: The Central Role for ER Contacts in Neuronal Function and Axonopathy, Lessons From Hereditary Spastic Paraplegias and Related Diseases

“…The interaction between Kv2 channels and VAPs seems to be an important determinant in the localization of these proteins in neurons with overexpression of Kv2.1 causing VAPs to redistribute to large ER-PM clusters while loss of VAPs reduce Kv2 clustering in the PM (Johnson et al, 2018; Kirmiz et al, 2018). Kv2 clusters in motor neurons can also be seen to be dynamic, redistributing into smaller clusters following neuronal activity (Romer et al, 2019).…”

Kcns3Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

“…Previous studies suggested that Kv2.1 channels regulate repetitive firing. For example, in layer 3 pyramidal cells and spinal motoneurons, Kv2.1 currents facilitate repetitive firing by preventing Na + channel inactivation (Guan et al, 2013;Romer et al, 2019). The FS phenotype of PV neurons, however, differs significantly from the firing patterns of pyramidal cells or motoneurons.…”

“…Next, we used the FS cell model to examine whether the strong stuttering phenotype produced by reduced levels of Kv2.1 conductance is associated with increased Na + channel inactivation, since Kv2.1 current was reported to facilitate repetitive firing by reducing Na + channel inactivation in other types of neurons (Guan et al, 2013;Romer et al, 2019). We Figure 5E).…”

“…In other types of neurons, Kv2.1 currents control spike frequency adaptation (Guan et al, 2013;Romer et al, 2019), suggesting that Kv2.1-Kv9.3 channels may contribute to the low spike frequency adaptation typical of FS cells (Hu et al, 2014). Therefore, in spike trains elicited by current steps in the experiments depicted in Figure 8, we assessed spike frequency adaptation by computing the ISIratio, or ratio between the last and first ISI, which is expected to produce values near 1 with low spike frequency adaptation.…”