Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Mounsey, J. Paul; Xu, Pu; John, J. Edward; Horne, Lauren; Gilbert, John R.; Roses, Allen D.; Moorman, J. Randall

doi:10.1172/jci117931

Cited by 51 publications

(35 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exons 12-15 specify this localization and for a higher order of self-association, which could be related. These results have implications with respect to the ability of DMK to modulate membrane-bound proteins, such as ion channels (30).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

Waring

Haq

Tamai

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

Myotonic dystrophy is caused by the expansion of a CTG repeat found in the 3-untranslated region of the myotonic dystrophy kinase. The mechanism of disease and the role of the kinase are currently obscure. Here we begin the investigation of domain structure/function correlations to aid in determining its normal function.Expressed full-length protein and protein truncated before a C-terminal hydrophobic domain were compared. In vitro, signal peptide function and protection of kinase by microsomal membranes were absent; thus, it is not translocated, as previously proposed. However, full-length kinase expressed in insect cells was found in fractions enriched for membranes and decorated mitochondria. The truncated form was found primarily in the cytosol. The kinase was present as two self-associated, disulfide-linked complexes. The majority of fulllength kinase was found in the larger of the two complexes, while almost all of the truncated form was found in the smaller. Thus, the C-terminal region confers a higher order of self-association. Furthermore, fulllength kinase expressed in COS-1 cells was present as high molecular weight complex, while the truncated form was present as monomer species. These experiments indicate that the myotonic dystrophy kinase is not membrane-integrated, but that it may have a molecular organization which favors peripheral association with membranes.

show abstract

Section: Discussionmentioning

confidence: 99%

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

Waring

Haq

Tamai

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…16,1996 Rho-BINDING KINASES AND CYTOSKELETON ORGANIZATION 5325 eration (4,8) probably as a result of its involvement in ion channel function (26), the fungal cot-1-encoded kinase required for controlling filamentous growth (41), and the recently reported Drosophila anti-oncogene warts gene product, which is essential for controlling cell growth and morphology during development (13). We have also isolated several ϳ180-kDa proteins containing related kinase domains which do not bind Rho but instead bind Cdc42 and Rac1 (17).…”

Section: Discussionmentioning

confidence: 99%

The p160 RhoA-Binding Kinase ROKα Is a Member of a Kinase Family and Is Involved in the Reorganization of the Cytoskeleton

Leung

Chen

Manser

et al. 1996

Molecular and Cellular Biology

835

737

View full text Add to dashboard Cite

The GTPase RhoA has been implicated in various cellular activities, including the formation of stress fibers, motility, and cytokinesis. We recently reported on a p150 serine/threonine kinase (termed ROK␣) binding RhoA only in its active GTP-bound state and on its cDNA; introduction of RhoA into HeLa cells resulted in translocation of the cytoplasmic kinase to plasma membranes, consistent with ROK␣ being a target for RhoA (T. Leung, E. Manser, L. Tan, and L. Lim, J. Biol. Chem. 256:29051-29054, 1995). Reanalysis of the cDNA revealed that ROK␣ contains an additional N-terminal region. We also isolated another cDNA which encoded a protein (ROK␤) with 90% identity to ROK␣ in the kinase domain. Both ROK␣ and ROK␤, which had a molecular mass of 160 kDa, contained a highly conserved cysteine/histidine-rich domain located within a putative pleckstrin homology domain. The kinases bound RhoA, RhoB, and RhoC but not Rac1 and Cdc42. The Rho-binding domain comprises about 30 amino acids. Mutations within this domain caused partial or complete loss of Rho binding. The morphological effects of ROK␣ were investigated by microinjecting HeLa cells with DNA constructs encoding various forms of ROK␣. Full-length ROK␣ promoted formation of stress fibers and focal adhesion complexes, consistent with its being an effector of RhoA. ROK␣ truncated at the C terminus promoted this formation and also extensive condensation of actin microfilaments and nuclear disruption. The proteins exhibited protein kinase activity which was required for stress fiber formation; the kinase-dead ROK␣K112A and N-terminally truncated mutants showed no such promotion. The latter mutant instead induced disassembly of stress fibers and focal adhesion complexes, accompanied by cell spreading. These effects were mediated by the C-terminal region containing Rho-binding, cysteine/histidine-rich, and pleckstrin homology domains. Thus, the multidomained ROK␣ appears to be involved in reorganization of the cytoskeleton, with the N and C termini acting as positive and negative regulators, respectively, of the kinase domain whose activity is crucial for formation of stress fibers and focal adhesion complexes.In mammals, the Ras-related Rho subfamily includes RhoA, -B, and -C, Rac1 and -2, and Cdc42, which play pivotal roles in cytoskeletal control and cell morphology. RhoA has been implicated in stress fiber formation (33, 34), whereas Rac1 (36) and Cdc42 (15,29) are involved in lamellipodial and filopodial formation, respectively. Fibroblasts injected with these GTPases display a set of distinctive morphological changes, suggestive of probable hierarchy in the order Cdc42, Rac, and Rho. These changes demand a high level of flexibility in the dynamic reorganization of actin microfilaments in cells. RhoA, -B, and -C have about 85% identity and appear to have different cellular localizations (1). Although their exact roles in cells have not been clearly defined, these GTPases have been implicated in a variety of cellular activities either directly by overexpression of wil...

show abstract

“…Disparate effects have been described in skeletal muscle and cardiac channels including acceleration of the current decay (Bendahhou et al 1995) and a hyperpolarizing shift in the steady-state availability curve . The skeletal muscle Na¤ channel is selectively phosphorylated by human myotonin protein kinase (HMPK) (Mounsey et al 1995;Chahine & George, 1997). Absent or reduced phosphorylation of skeletal muscle Na¤ channels by mutant HMPK may underlie the altered excitability of muscle in myotonic dystrophy, but, curiously, the genetic alterations do not appear to alter kinase function (Mounsey et al 1995).…”

Section: Post-translational Modification: Phosphorylationmentioning

confidence: 99%

Structure and function of voltage‐gated sodium channels

Marbán

Yamagishi

Tomaselli

1998

The Journal of Physiology

303

186

View full text Add to dashboard Cite

Sodium channels mediate fast depolarization and conduct electrical impulses throughout nerve, muscle and heart. This paper reviews the links between sodium channel structure and function. Sodium channels have a modular architecture, with distinct regions for the pore and the gates. The separation is far from absolute, however, with extensive interaction among the various parts of the channel. At a molecular level, sodium channels are not static: they move extensively in the course of gating and ion translocation. Sodium channels bind local anaesthetics and various toxins. In some cases, the relevant sites have been partially identified. Sodium channels are subject to regulation at the levels of transcription, subunit interaction and post‐translational modification (notably glycosylation and phosphorylation).

show abstract

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Cited by 51 publications

References 50 publications

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

The p160 RhoA-Binding Kinase ROKα Is a Member of a Kinase Family and Is Involved in the Reorganization of the Cytoskeleton

Structure and function of voltage‐gated sodium channels

Contact Info

Product

Resources

About