Modeling interactions between voltage-gated Ca²⁺channels and KCa1.1 channels

Abstract

High voltage-activated (HVA) Cav channels form complexes with KCa1.1 channels, allowing reliable activation of KCa1.1 current through a nanodomain interaction. We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes. While coimmunoprecipitation studies again supported a nanodomain interaction, the sensitivity to calcium chelating agents was instead consistent with a microdomain interaction. A computational model of the KCa1.1-Cav3 complex suggested that multiple Cav3 channels were necessary to activate KCa1.1 channels, potentially causing the KCa1.1-Cav3 complex to be more susceptible to calcium chelators. Here, we expanded the model and compared it to a KCa1.1-Cav2.2 model to examine the role of Cav channel conductance and kinetics on KCa1.1 activation. As found for direct recordings, the voltage-dependent and kinetic properties of Cav3 channels were reflected in the activation of KCa1.1 current, including transient activation from lower voltages than other KCa1.1-Cav complexes. Substantial activation of KCa1.1 channels required the concerted activity of several Cav3.2 channels. Combined with the effect of EGTA, these results suggest that the Ca2+ domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca2+]i, despite the physical association between KCa1.1 and Cav3 channels. By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient. However, even though Cav3 channels generate small, transient currents, the regulation of KCa1.1 activity by Cav3 channels is possible if multiple complexes cooperate through microdomain interactions.

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

“…Control of neuronal excitability depends on calcium-dependent afterhyperpolarizations (AHPs) that activate over specific time frames, ranging from rapid spike repolarization (in milliseconds) to long-duration slow AHPs (in seconds). This level of precision is enabled by functional coupling between specific isoforms of calcium-gated potassium channels and the underlying calcium source (Berkefeld and Fakler, 2008;Engbers et al, 2012Engbers et al, , 2013bMarrion and Tavalin, 1998;Vivas et al, 2017). As a result, the properties of AHPs can reflect the voltage-dependent properties of both the calcium source and the potassium channel (Berkefeld and Fakler, 2008;Engbers et al, 2013b).…”

“…This level of precision is enabled by functional coupling between specific isoforms of calcium-gated potassium channels and the underlying calcium source (Berkefeld and Fakler, 2008;Engbers et al, 2012Engbers et al, , 2013bMarrion and Tavalin, 1998;Vivas et al, 2017). As a result, the properties of AHPs can reflect the voltage-dependent properties of both the calcium source and the potassium channel (Berkefeld and Fakler, 2008;Engbers et al, 2013b). Specific combinations of channel isoforms thus combine to drive a fast AHP (fAHP) (Gu et al, 2007;Shao et al, 1999), medium AHP (mAHP) (Adelman et al, 2012;Gu et al, 2005;Tzingounis and Nicoll, 2008), or slow AHP (sAHP) (Bodhinathan et al, 2010;Cloues et al, 1997;Gamelli et al, 2011;Kim et al, 2007;King et al, 2015;Lancaster and Nicoll, 1987;Sahu et al, 2017;Thibault and Landfield, 1996;van de Vrede et al, 2007).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…In the SAN, Ca V 3 channels also contribute to pacemaker activity (Mangoni et al, 2006). Finally, T-type calcium channels have been shown to be associated physically and functionally with members of voltage-and calciumactivated potassium channels (Anderson et al, , 2013Engbers et al, 2012Engbers et al, , 2013Rehak et al, 2013). These associations confer T-type channel-mediated calcium-dependent control of potassium channel activity, which in turn regulates neuronal firing patterns (Turner and Zamponi, 2014).…”

Down-regulation of T-type Cav3.2 channels by hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1): Evidence of a signaling complex

“…For Kv4 channels and calcium-activated potassium channels, the association with Cav3 was shown to confer a potent calcium regulation on potassium channel function. 9,[20][21][22][23][24] For HCN1, our data indicate that this does not appear the case, at least not in expression systems. Unlike Kv4 channels which interact with KChIPs 23 and calcium-activated potassium channels which either contain calcium sensors, or are conjugated to calmodulin, 25 there appear to be no such processes in place for calcium regulation of HCN channels.…”

“…9,[20][21][22][23][24] The channel structural determinants of these interactions have been delineated and shown to involve either the C-terminus region of Cav3 (Kv4), 23 or transmembrane regions (BK). 9 Here, we report an interaction that involves the N-terminus region of Cav3.2.…”