Abstract
The voltage-gated K+ channel Kv2.1 serves a major structural role in the soma and proximal dendrites of mammalian brain neurons, tethering the plasma membrane (PM) to endoplasmic reticulum (ER). Although Kv2.1 clustering at neuronal ER-PM junctions (EPJs) is tightly regulated and highly conserved, its function remains unclear. By identifying and evaluating proteins in close spatial proximity to Kv2.1-containing EPJs, we discovered that a significant role of Kv2.1 at EPJs is to promote the clustering and functional coupling of PM L-type Ca2+ channels (LTCCs) to ryanodine receptor (RyR) ER Ca2+ release channels. Kv2.1 clustering also unexpectedly enhanced LTCC opening at polarized membrane potentials. This enabled Kv2.1-LTCC-RyR triads to generate localized Ca2+ release events (i.e., Ca2+ sparks) independently of action potentials. Together, these findings uncover a novel mode of LTCC regulation and establish a unique mechanism whereby Kv2.1-associated EPJs provide a molecular platform for localized somatodendritic Ca2+ signals in mammalian brain neurons.
Highlights
The members of the Kv2 family of voltage-gated K+ (Kv) channels, Kv2.1 and Kv2.2, are among the most abundant and widely expressed K+ channels in mammalian brain neurons (Trimmer, 2015)
Triple immunolabeling for Kv2.1, Cav1.2, and ryanodine receptor (RyR) demonstrated that many of the clusters of spatially associated Kv2.1 and Cav1.2 channels were colocalized with RyRs (Figure 1C)
In support of a spatial association between Kv2.1, Cav1.2, and RyRs, we determined that there was a positive correlation between the Pearson’s Correlation Coefficient (PCC) of Kv2.1 and Cav1.2, and the PCC of Cav1.2 and RyRs within the same cell (Figure 1F), suggesting that increased association between Cav1.2 and Kv2.1 was associated with greater spatial coupling of Cav1.2 to RyRs
Summary
The members of the Kv2 family of voltage-gated K+ (Kv) channels, Kv2.1 and Kv2.2, are among the most abundant and widely expressed K+ channels in mammalian brain neurons (Trimmer, 2015). Kv2 channels are present in high-density clusters localized to neuronal somata, proximal dendrites, and axon initial segments (Trimmer, 1991; Du et al, 1998; Bishop et al, 2015; Kirmiz et al, 2018a). In hippocampal and cortical neurons, Kv2 channels conduct most of the delayed rectifier K+ current (Murakoshi and Trimmer, 1999; Du et al, 2000; Guan et al, 2007). Kv2.1 clustering at EPJs is tightly regulated and independent of K+ conductance (Kirmiz et al, 2018b), the physiological impact of concentrating this Kv channel at an EPJ is not known
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