Abstract
The L‐type CaV1.2 channel plays an essential role in gene expression, cell excitability and muscle contraction. These channels clustered throughout the plasma membrane of excitable and non‐excitable cells. This has been suggested to contribute to regional variations in channel activity and the concerted opening and closing of adjacent CaV1.2 channels (e.g. cooperative gating), but whether dynamic intracellular and near‐membrane trafficking of the channel modulates these features is unknown. Here we show dynamic transport of CaV1.2 in vesicles of circular and tubular shape with diverse intracellular and submembrane trafficking patterns. Microtubules and actin filaments are required for dynamic movement of CaV1.2 vesicles, which undergo constitutive homotypic fusion and fission events to sustain CaV1.2 clustering, channel activity and cooperative gating. In conclusion, our study reveals very diverse and unique intracellular and near‐membrane dynamics of the CaV1.2 channel in which homotypic vesicle fusion may be a key event promoting CaV1.2 membrane organization and clustering to facilitate its physical proximity for cooperative gating and fine‐tune control of Ca2+ signals.Support or Funding InformationNIHRO1HL098200, NIHRO1HL121059This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Highlights
The L-type CaV1.2 channel is expressed in many cells where it plays an indispensable role in multiple physiological processes [1]
These results suggest that CaV1.2 channels preferentially cluster in structures that are fed by cytoskeleton-dependent trafficking of CaV1.2 vesicles in areas at/near the plasma membrane
We found that whole-cell ICa elicited by a depolarizing step from−70 mV to 0 mV, were significantly smaller in cells co-treated with nocodazole + cytochalasin D (cyt-D) compared to vehicle-treated cells (Fig. 7C)
Summary
The L-type CaV1.2 channel is expressed in many cells where it plays an indispensable role in multiple physiological processes [1]. CaV1.2-containing vesicles undergo constitutive homotypic fusion and fission events with each other at/near the plasma membrane and throughout the intracellular compartment requiring trafficking via both actin filaments and microtubules. This directed trafficking maintains a pool of vesicles containing channels just underneath the surface membrane that along with fusion events facilitates CaV1.2 clustering, channel activity and functional cooperative gating between channels. These observations may have important implications for Ca2+ homeostasis in a number of physiological processes
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