| First Author | Lubbers ER | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 24 | Pages | 9576-9591 |
| PubMed ID | 31064843 | Mgi Jnum | J:281018 |
| Mgi Id | MGI:6368729 | Doi | 10.1074/jbc.RA119.007714 |
| Citation | Lubbers ER, et al. (2019) Defining new mechanistic roles for alphaII spectrin in cardiac function. J Biol Chem 294(24):9576-9591 |
| abstractText | Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. alphaII spectrin (SPTAN1) is one of two alpha spectrin genes and alphaII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human alphaII spectrin loss-of-function variants cause neurological disease. As global alphaII spectrin knockout mice are embryonic lethal, the in vivo roles of alphaII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in alphaII spectrin regulation in human heart failure we tested the in vivo roles of alphaII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective alphaII spectrin-deficiency (cKO) and used this model to define the roles of alphaII spectrin in cardiac function. alphaII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that alphaII spectrin plays a nodal role for global cardiac spectrin regulation, as alphaII spectrin cKO hearts exhibited remodeling of alphaI spectrin and altered beta-spectrin expression and localization. At the cellular level, alphaII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels NaV1.5 and KV4.3. In summary, our findings define critical and unexpected roles for the multifunctional alphaII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of alphaII spectrin in the cardiomyocyte. |
