Ferlins: Regulators of Vesicle Fusion for Auditory Neurotransmission, Receptor Trafficking and Membrane Repair

Lek, Angela; Evesson, Frances J.; Sutton, R. Bryan; North, Klaus; Cooper, Sandra T.

doi:10.1111/j.1600-0854.2011.01267.x

Cited by 124 publications

(126 citation statements)

References 90 publications

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“…Dysferlin is a single-pass transmembrane protein containing multiple cytoplasmic C2 domains, and is a member of the evolutionarily conserved ferlin family of proteins. Ferlin proteins play a critical role in membrane fusion across multiple species and cell types (6). Dysferlin appears to have evolved in higher order vertebrates and is relatively muscle specific, with the highest expression in mature skeletal and cardiac muscle (7).…”

Section: Introductionmentioning

confidence: 99%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

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Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystrophy 2B and Myoshi myopathy in humans. Dysferlin has been proposed as a critical regulator of vesicle-mediated membrane resealing in muscle fibers, and localizes to muscle fiber wounds following sarcolemma damage. Studies in fibroblasts and urchin eggs suggest that trafficking and fusion of intracellular vesicles with the plasma membrane during resealing requires the intracellular cytoskeleton. However, the contribution of dysferlin-containing vesicles to resealing in muscle and the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear. Here, we use live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular wounding in muscle cells and examine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding. Our data indicate that dysferlin-containing vesicles move along microtubules via the kinesin motor KIF5B in muscle cells. Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the formation of extremely large cytoplasmic vesicles, and this response depends on both microtubules and functional KIF5B. In non-muscle cell types, lysosomes are critical mediators of membrane resealing, and our data indicate that dysferlincontaining vesicles are capable of fusing with lysosomes following wounding which may contribute to formation of large wound sealing vesicles in muscle cells. Overall, our data provide mechanistic evidence that microtubulebased transport of dysferlin-containing vesicles may be critical for resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organelle fusion in response to wounding in muscle cells.

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Section: Introductionmentioning

confidence: 99%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

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“…It is a membrane-spanning protein with multiple C2 domains that bind calcium, phospholipids, and proteins to set off signaling events, vesicle trafficking, and membrane fusion [1,2]. In both skeletal and cardiac muscle cells dysferlin plays a decisive role in calcium-dependent membrane repair [3][4][5]. Consequently, injuries of the sarcolemma trigger the accumulation of dysferlin-enriched membrane patches and resealing of the membrane [3].…”

Section: Introductionmentioning

confidence: 99%

Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Rubi

Gawali

Kubista

et al. 2015

Cell Physiol Biochem

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Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.

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“…Sequence analyses have revealed that while MCTPs are evolutionarily conserved (Nalefski 90 and Falke, 1996;Shin et al, 2005;Lek et al, 2012;Liu et al, 2013), there is a significantly 91 increased number of MCTP repertoire in the plant lineage compared to the number of 92 counterparts in animals. This implies more diverse and specific functions of MCTPs in…”

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confidence: 99%

Characterization of Multiple C2 Domain and Transmembrane Region Proteins in Arabidopsis

Liu

Liang

et al. 2017

Plant Physiol.

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Ferlins: Regulators of Vesicle Fusion for Auditory Neurotransmission, Receptor Trafficking and Membrane Repair

Cited by 124 publications

References 90 publications

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Characterization of Multiple C2 Domain and Transmembrane Region Proteins in Arabidopsis

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