BIN1 clusters CaV1.2 channels in vascular smooth muscle

Abstract

Resistance vessel such as mesenteric arteries respond to increases in intravascular pressure by constricting. Ca2+ influx via voltage‐gated CaV1.2 channels in the smooth muscle surrounding these vessels is critical for the development of myogenic tone and thus the regulation of arterial dimeter and blood flow. Our group discovered that CaV1.2 channels have an inherent ability to form clusters and functionally couple in response to local elevations in [Ca2+]i. The consequence of these channels coming together is that they amplify Ca2+ influx during depolarization. However, the mechanisms dictating the arrangement of CaV1.2 channels in smooth muscle cells are unknown. BIN1, a member of the BAR (Bin1‐Amphiphysin‐Rvs) domain superfamily, has been implicated in the trafficking of CaV1.2 channels but has not yet been studied in smooth muscle. In this study, we test the hypothesis that BIN1 promotes the formation of CaV1.2 clusters enhancing overall Ca2+ influx into the vascular smooth muscle and shaping arterial diameter. We report that BIN1 is expressed and translated in arterial smooth muscle while ground state depletion (GSD) super‐resolution imaging suggest that smooth muscle specific down‐regulation of BIN1 diminishes CaV1.2 cluster formation. Using patch clamp electrophysiology and pressurized arteriography, we observed that loss of BIN1 substantially diminishes ICa and attenuates arterial tone. Overall, these results suggest that BIN1 is a critical component in shaping CaV1.2 clustering and plays a physiological role in vascular smooth muscle Ca2+ entry and arterial diameter.Support or Funding InformationThis work is supported by NIH R01 HL085870 (LFS), T32GM099608 (SO), and 18PRE33960249 (SO)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.