Abstract
Author SummaryCalcium plays a primary role in regulating heart function. During each heartbeat, calcium ions cross the membrane of individual cardiac muscle cells and trigger a rapid increase of calcium within the cell (called the calcium transient). Calcium causes the muscle cells to contract and determines the strength of the overall heartbeat. Each cardiac muscle cell has many small tubular-like membrane invaginations known as T-tubules where calcium channels localize, allowing calcium ions to enter and immediately encounter intracellular calcium release organelles. While this organization is well described, it is not known how calcium channels localize to T-tubule membrane. Here we show that in human and mouse heart cells, a membrane scaffolding protein known as BIN1 is localized together with calcium channels at T-tubules. Using high-resolution live cell microscopy, we found that microtubules, which are necessary for calcium channel delivery to the membrane, are also tethered by BIN1. Loss of BIN1 in cardiac cells impairs delivery of calcium channels to the membrane and diminishes the intracellular calcium transient. According to this model, microtubules function as highways that carry newly synthesized calcium channels to BIN1-containing membrane. Once tethered to T-tubules by BIN1, the microtubules can deliver their calcium channel cargo. We postulate that this calcium channel delivery pathway is important to the regulation of cardiac calcium signaling and beat-to-beat cardiac function.
Highlights
The BAR domain superfamily is composed of proteins involved in endocytosis, organelle biogenesis, cell division, and cell migration
Calcium ions cross the membrane of individual cardiac muscle cells and trigger a rapid increase of calcium within the cell
Each cardiac muscle cell has many small tubular-like membrane invaginations known as T-tubules where calcium channels localize, allowing calcium ions to enter and immediately encounter intracellular calcium release organelles
Summary
The BAR domain superfamily is composed of proteins involved in endocytosis, organelle biogenesis, cell division, and cell migration (review in [1]). As a member of the BAR domain superfamily, the tubulogenesis membrane scaffolding protein BIN1 (Amphiphysin 2) is known to induce membrane invagination [2,3] and initiate tubulogenesis in skeletal muscle cells [4]. Knowledge of the role of BIN1 in muscle cells includes evidence of BIN1 distribution on T-tubules of skeletal myocytes [4] and that constitutive knockdown of BIN1 in mice is perinatal lethal, with pathology revealing a hypertrophic dilated cardiomyopathy [6,7]. Despite these findings, little is known of the functional role of BIN1 in cardiomyocytes. A major function of T-tubule invaginations of the sarcolemma, which are enriched with Cav1.2 channels [10,11], is to bring the channels into close
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