Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage

Abstract

CaV-channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and CaV1.3 channels, unique CaV1 channels that activate at low voltages. We found that when BK and CaV1.3 channels were co-expressed in the same cell, BK channels started activating near −50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated CaV2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of CaV1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of CaV1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials.DOI: http://dx.doi.org/10.7554/eLife.28029.001

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Nav1.5

“…This coupling is increased by ß-adrenergic stimulation 2 . In the brain, functional coupling has been shown for BK and Ca v 1.3 channels, and cooperative gating has been suggested to play a role in short-term memory 2,53 . Lastly, voltage-gated proton channels that are expressed in many organisms and tissues are also shown to gate cooperatively 2-56 .…”

A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels

“…It is important to note that, unlike the case of CaM actions on VGCCs, for which highly local free [Ca 2ϩ ] at the inner mouth of the pore may approach millimolar concentrations (16,78,79), no Ca 2ϩ ions are flowing through open K ϩ channels, and so it is likely that, as for the analysis of CaM actions on SK K ϩ channels, it is global [Ca 2ϩ ] that should be most relevant for our thinking. This supposition is tempered, however, by the discovery of KCNQ channels and Ca 2ϩ -permeable channels clustered together in microdomains in sensory neurons (80), and similar multichannel complexes likely exist in brain as well (81)(82)(83). Thus, we cannot say with certainty the precise [Ca 2ϩ ] in the local micro-environment of KCNQ channels in nerve, heart, and muscle that corresponds to CaM being maximally "switched on.…”

Modulation of Function, Structure and Clustering of K+ Channels by Lipids: Lessons Learnt from KcsA

“…Experimental data from other ion channels of excitable membranes, such as those in the heart and the nervous system, including the mammalian brain, also exhibit cooperative properties modulated by lipids, which are suggestive of clustering processes similar to that in KcsA [93][94][95][96][97][98][99][100][101][102][103]. This is to conclude that lipid-dependent processes such as those found in the KcsA model could be present in many other membrane proteins, including different ion channels.…”