| First Author | Hashad AM | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 10 | Pages | 2371-2381 |
| PubMed ID | 30354206 | Mgi Jnum | J:285179 |
| Mgi Id | MGI:6385500 | Doi | 10.1161/ATVBAHA.118.311394 |
| Citation | Hashad AM, et al. (2018) Caveolae Link CaV3.2 Channels to BKCa-Mediated Feedback in Vascular Smooth Muscle. Arterioscler Thromb Vasc Biol 38(10):2371-2381 |
| abstractText | Objective- This study examined whether caveolae position CaV3.2 (T-type Ca2+ channel encoded by the alpha-3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca(2+) influx to trigger Ca(2+) sparks and large-conductance Ca(2+)-activated K(+) channel feedback. Approach and Results- Using smooth muscle cells from mouse mesenteric arteries, the proximity ligation assay confirmed that CaV3.2 reside within 40 nm of caveolin 1, a key caveolae protein. Methyl-beta-cyclodextrin, a cholesterol depleting agent that disrupts caveolae, suppressed CaV3.2 activity along with large-conductance Ca(2+)-activated K(+)-mediated spontaneous transient outward currents in cells from C57BL/6 but not CaV3.2(-/-) mice. Genetic deletion of caveolin 1, a perturbation that prevents caveolae formation, also impaired spontaneous transient outward current production but did so without impairing Ca(2+) channel activity, including CaV3.2. These observations indicate a mistargeting of CaV3.2 in caveolin 1(-/-) mice, a view supported by a loss of Ni(2+)-sensitive Ca(2+) spark generation and colocalization signal (CaV3.2-RyR) from the proximity ligation assay. Vasomotor and membrane potential measurements confirmed that cellular disruption of the CaV3.2-RyR axis functionally impaired the ability of large-conductance Ca(2+)-activated K(+) to set tone in pressurized caveolin 1(-/-) arteries. Conclusions- Caveolae play a critical role in protein targeting and preserving the close structural relationship between CaV3.2 and RyR needed to drive negative feedback control in resistance arteries. |
