Signal processing by T-type calcium channel interactions in the cerebellum

Abstract

T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT) and hyperpolarization-activated cation current (IH) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect effects on membrane properties.

Junctophilin Proteins Tether a Cav1-RyR2-KCa3.1 Tripartite Complex to Regulate Neuronal Excitability

“…JPHs Enable Cav1-RyR-KCa3.1 Interactions The properties of AHPs can reflect those of both the calcium source and the potassium channel, with control refined by pairing different channel isoforms (Anderson et al, 2010;Berkefeld and Fakler, 2008;Engbers et al, 2012Engbers et al, , 2013aMarrion and Tavalin, 1998;Vivas et al, 2017). Here we define an additional role for JPH3 and JPH4 that enables the functional coupling of Cav1.3 and KCa3.1 channels in the PM to RyRs in the ER of hippocampal neurons.…”

BK Channels in the Central Nervous System

“…For instance, Ca 2+ entry via fast-activating P/Q- and N-type channels in presynaptic terminals can indirectly, via a BK channel-dependent shortening of AP duration, reduce neurotransmitter release (Castillo, Weisskopf, & Nicoll, 1994; Kulik et al, 2004; Pelkey, Topolnik, Lacaille, & McBain, 2006; Wu, Westenbroek, Borst, Catterall, & Sakmann, 1999). Alternatively, the more slowly activating L- and T-type channels located primarily in the dendrites and cell body have been shown to gate BK channels and thereby regulate their role in synaptic summation and AP propagation (Dobremez et al, 2005; Engbers, Anderson, Zamponi, & Turner, 2013; Obermair, Szabo, Bourinet, & Flucher, 2004; Rehak et al, 2013). …”

“…In cortical pyramidal neurons, both N- and L-type channels provide Ca 2+ to gate BK channel opening (Sun et al, 2003), while in chromaffin cells, L- and P/Q-type channels play a greater role than N-type channels in gating BK channels (Prakriya & Lingle, 1999). Additionally, low-voltage-activated T-type channels in cerebellar neurons complex with BK channels to reduce synaptically evoked neural firing (Engbers et al, 2013). By associating with a diverse set of Ca V partners, BK channels can adapt to display diverse temporal responses that may enable them to serve different roles in regulating neural activity (Berkefeld & Fakler, 2008).…”

The truth in complexes: perspectives on ion channel signaling nexuses in the nervous system

“…With respect to DPLPs and KChIPs, further study has also shed new light on their molecular diversity via alternative splicing as well as their roles in regulating several other channel types, such as voltage-gated Ca 2+ channels and NMDARs. Connecting K + channels with voltage-gated Ca 2+ channels, Engbers et al ( 2013 ) review how channel-channel interactions between intermediate conductance Ca 2+ -activated K + channels (IKCa) and low voltage-activated Ca 2+ channels (Cav3) functionally interact with other conductances to regulate signal processing in the cerebellum.…”