Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, United States; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, United States
Michael Kirmiz
Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, United States
Deborah van der List
Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, United States; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, United States
Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, United States; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, United States
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.
