Use-Dependent Activation of Neuronal Kv1.2 Channel Complexes

Abstract

In excitable cells, ion channels are frequently challenged by repetitive stimuli, and their responses shape cellular behavior by regulating the duration and termination of bursts of action potentials. We have investigated the behavior of Shaker family voltage-gated potassium (Kv) channels subjected to repetitive stimuli, with a particular focus on Kv1.2. Genetic deletion of this subunit results in complete mortality within 2 weeks of birth in mice, highlighting a critical physiological role for Kv1.2. Kv1.2 channels exhibit a unique property described previously as "prepulse potentiation," in which activation by a depolarizing step facilitates activation in a subsequent pulse. In this study, we demonstrate that this property enables Kv1.2 channels to exhibit use-dependent activation during trains of very brief depolarizations. Also, Kv subunits usually assemble into heteromeric channels in the central nervous system, generating diversity of function and sensitivity to signaling mechanisms. We demonstrate that other Kv1 channel types do not exhibit use-dependent activation, but this property is conferred in heteromeric channel complexes containing even a single Kv1.2 subunit. This regulatory mechanism is observed in mammalian cell lines as well as primary cultures of hippocampal neurons. Our findings illustrate that use-dependent activation is a unique property of Kv1.2 that persists in heteromeric channel complexes and may influence function of hippocampal neurons.

Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions

“…depolarizing shift in the half-maximal activation (Watanabe et al, 2007). Typical features of Kv1.2 are the low threshold (below action potential threshold) and the use-dependent activation (Baronas et al, 2015). Thus, Kv1.2 is activated before the action potential is elicited, and repetitive firing may increase Kv1.2 contribution to AP repolarization.…”

“…However, Kv1.2 channels can be divided into slow and fast gating channels (Rezazadeh et al, 2007), and it is uncertain to what extent gating properties observed in expression systems can be transferred to presynaptic terminals. But for the dendritic Kv1.2 channels together with the use-dependent activation of Kv1.2 (Baronas et al, 2015), it is possible that the patient's antibody shifts the slow gating channel into the fast gating one. Interestingly, both loss-of-function and gain-of-function mutations of the Kv1.2-encoding gene, KCNA2, were associated with epileptic encephalopathy (Syrbe et al, 2015).…”

“…differences obtained (especially action potential characteristics and afterhyperpolarizing potential) are not compatible with an impaired K + channel function of CA1 neurons, but may rather indicate separate changes on the network level. In addition, one unique property of Kv1.2, but not of other Kv1 channels, is the use-dependent activation (Baronas et al, 2015). Hence, we prolonged the current injection to 600 ms (500 pA) with an interstimulus interval of 10 s. Under these conditions, we observed that CA1 cells from anti-Kv1.2 showed a significantly reduced number of action potentials compared to control (P < 0.05, two-way ANOVA with factors current injection and animal group, followed by Tukey post hoc test; Figure 3A).…”

Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

“…Based on prior observations of variable Kv1.2 function in different cell types, we hypothesized that Kv1.2 is influenced by a variety of unidentified regulators (Abraham et al, 2019;Baronas et al, 2017Baronas et al, , 2016Baronas et al, , 2015Rezazadeh et al, 2007) . We have pursued the identification of novel regulatory proteins that may influence this widely used model Kv channel.…”

Extracellular redox sensitivity of Kv1.2 potassium channels

“…Thus, it has served as an essential structural template for the interpretation of functional data in a variety of ion channel types, and for the generation and simulation of in silico models of ion channels. Despite the understanding implied by the precision of an atomic resolution structure, there is remarkable variability of Kv1.2 gating behavior in different experimental reports and expression systems, suggesting a regulatory mechanism that has yet to be described 5 – 9 .…”