Localization of the α1 and α2 subunits of the dihydropyridine receptor and ankyrin in skeletal muscle triads

Flucher, Bernhard E.; Morton, M. E.; Froehner, Stanley C.; Daniels, Mathew P.

doi:10.1016/0896-6273(90)90170-k

Cited by 83 publications

(55 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6A, insets) were continuous with DHPR and with the same spacing and were slightly narrower than double rows of ryanodine receptor that mark the sarcoplasmic reticulum at the triad junction (data not shown). In mammalian skeletal muscle, there are two closely spaced transverse tubules per sarcomere, and the striated Kir2.1 labeling pattern is consistent with localization at T-tubules (47). Altogether the data suggest that endogenous Kir2.1 is abundant on the plasma membrane and on T-tubules near the periphery of muscle fibers and with lower abundance on T-tubules in the center of fibers.…”

Section: Kir22 Proline 156 Is a Critical Determinant Of Channelsupporting

confidence: 65%

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Dassau

Conti

Radeke

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Precise trafficking, localization, and activity of inward rectifier potassium Kir2 channels are important for shaping the electrical response of skeletal muscle. However, how coordinated trafficking occurs to target sites remains unclear. Kir2 channels are tetrameric assemblies of Kir2.x subunits. By immunocytochemistry we show that endogenous Kir2.1 and Kir2.2 are localized at the plasma membrane and T-tubules in rodent skeletal muscle. Recently, a new subunit, Kir2.6, present in human skeletal muscle, was identified as a gene in which mutations confer susceptibility to thyrotoxic hypokalemic periodic paralysis. Here we characterize the trafficking and interaction of wild type Kir2.6 with other Kir2.x in COS-1 cells and skeletal muscle in vivo. Immunocytochemical and electrophysiological data demonstrate that Kir2.6 is largely retained in the endoplasmic reticulum, despite high sequence identity with Kir2.2 and conserved endoplasmic reticulum and Golgi trafficking motifs shared with Kir2.1 and Kir2.2. We identify amino acids responsible for the trafficking differences of Kir2.6. Significantly, we show that Kir2.6 subunits can coassemble with Kir2.1 and Kir2.2 in vitro and in vivo. Notably, this interaction limits the surface expression of both Kir2.1 and Kir2.2. We provide evidence that Kir2.6 functions as a dominant negative, in which incorporation of Kir2.6 as a subunit in a Kir2 channel heterotetramer reduces the abundance of Kir2 channels on the plasma membrane.Inward rectifier potassium (Kir2) channels are key skeletal muscle components involved in determination of muscle resting potential, regulation of electrical excitability, repolarization of the action potential, and clearance of K ϩ from the T-tubule 2 system (1-4 Recently, a search for genes involved in thyrotoxic periodic paralysis (TPP) revealed KCNJ18, which encodes a novel subtype of inward rectifier potassium channel subunit, Kir2.6 (22). Kir2.6 is expressed primarily in skeletal muscle and shares Ͼ98% identity with Kir2.2 (22). Mutations in human Kir2.6 confer susceptibility to TPP, and it has been shown that these disease-associated mutations contribute to atypical current signatures and altered cell excitability (22). Expression studies in heterologous cells demonstrate that Kir2.6 subunits are able to form inwardly rectifying channels and that disease-associated mutations include truncated subunits that do not form functional channels, as well as gain-of-function mutations that increase electrical activity because of misregulation by phosphorylation (22).In addition to their electrophysiological properties, ion channels contribute to electrical events by their abundance on the plasma membrane. Targeting ion channels to subcellular sites and the plasma membrane is important for shaping the electrical response of muscle. Surface expression levels and channel activity are crucial for determining muscle excitability. However, trafficking of Kir2.6 to the plasma membrane has not yet been explored. Moreover, the role of wild type Kir2.6 in normal...

show abstract

Section: Kir22 Proline 156 Is a Critical Determinant Of Channelsupporting

confidence: 65%

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Dassau

Conti

Radeke

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Studies localizing C subunit and the L-type Ca 2ϩ channel in both wild-type and RII␣ knockout cultured skeletal muscle cells support the conclusion that PKA is anchored near the L-type Ca 2ϩ channel in skeletal muscle. In developing myotubes that are not cross-striated, the C subunit and L-type Ca 2ϩ channel are diffusely distributed, similar to the pattern of the ␣ 1 subunit of the L-type Ca 2ϩ channel described previously (29,30). In longer term cultures of differentiated myotubes containing cross-striations, the C subunit and the L-type Ca 2ϩ channel appear to be preferentially localized to the transverse tubules ( Fig.…”

Section: Discussionmentioning

confidence: 58%

Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca ²⁺ channel activity by cAMP-dependent protein kinase

Burton

Johnson

Hausken

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

124

View full text Add to dashboard Cite

Preferential phosphorylation of specific proteins by cAMP-dependent protein kinase (PKA) may be mediated in part by the anchoring of PKA to a family of A-kinase anchor proteins (AKAPs) positioned in close proximity to target proteins. This interaction is thought to depend on binding of the type II regulatory (RII) subunits to AKAPs and is essential for PKA-dependent modulation of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid͞kainate receptor, the L-type Ca 2؉ channel, and the K Ca channel. We hypothesized that the targeted disruption of the gene for the ubiquitously expressed RII␣ subunit would reveal those tissues and signaling events that require anchored PKA. RII␣ knockout mice appear normal and healthy. In adult skeletal muscle, RI␣ protein levels increased to partially compensate for the loss of RII␣. Nonetheless, a reduction in both catalytic (C) subunit protein levels and total kinase activity was observed. Surprisingly, the anchored PKA-dependent potentiation of the L-type Ca 2؉ channel in RII␣ knockout skeletal muscle was unchanged compared with wild type although it was more sensitive to inhibitors of PKA-AKAP interactions. The C subunit colocalized with the L-type Ca 2؉ channel in transverse tubules in wild-type skeletal muscle and retained this localization in knockout muscle. The RI␣ subunit was shown to bind AKAPs, although with a 500-fold lower affinity than the RII␣ subunit. The potentiation of the L-type Ca 2؉ channel in RII␣ knockout mouse skeletal muscle suggests that, despite a lower affinity for AKAP binding, RI␣ is capable of physiologically relevant anchoring interactions.Following the hormonal elevation of cAMP, phosphorylation of protein substrates by cAMP-dependent protein kinase (PKA) influences many physiological processes, including cellular differentiation, metabolism, and ion channel activity. PKA is a holoenzyme consisting of two regulatory (R) and two catalytic (C) subunits. Multiple subunits have been identified for R (RI␣, RI␤, RII␣, and RII␤) and C (C␣, C␤, and C␥) subunits. In general, the ␣ isoforms are constitutively expressed in most tissues, whereas the ␤ isoforms are highly expressed in the brain with a lower and more selective expression in other tissues (1). Despite the ubiquitous expression of PKA, cells are capable of specific responses to hormones and neurotransmitters. It has been proposed that the selective phosphorylation of specific proteins by PKA is achieved in part by the subcellular compartmentalization of PKA (2).The RII subunits (RII␣ and RII␤) are postulated to anchor PKA holoenzyme to subcellular compartments thereby positioning PKA in close proximity to its substrates (3). In support of this, RII subunits have been shown to bind to a family of A-kinase anchor proteins (AKAPs) (4, 5). These AKAPs contain a conserved amphipathic helix that binds to the amino terminus of the RII subunit (5, 6). In addition to binding to the RII subunit of PKA, AKAP 79 interacts with the calcium and calmodulin-dependent protein phosphatase 2B (calcineurin...

show abstract

“…The submembranous cytoskeletal protein ankyrin 3 localizes to what appear to be the same bands as Bin1ϩ10ϩ13 within the muscle fiber (23). Ankyrin 3 is a specific marker for invaginations of the muscle cell plasmalemma known as transverse (T)-tubules (79). That Bin1ϩ10ϩ13 localizes to T-tubules in muscle was confirmed by colocalization with another T-tubule-specific marker, triadin (108), and immunoelectron microscopy of ultrathin skeletal muscle frozen sections (23).…”

Section: Waf1mentioning

confidence: 76%

The BAR Domain Proteins: Molding Membranes in Fission, Fusion, and Phagy

Ren

Vajjhala

Lee

et al. 2006

Microbiol Mol Biol Rev

194

186

View full text Add to dashboard Cite

SUMMARY The Bin1/amphiphysin/Rvs167 (BAR) domain proteins are a ubiquitous protein family. Genes encoding members of this family have not yet been found in the genomes of prokaryotes, but within eukaryotes, BAR domain proteins are found universally from unicellular eukaryotes such as yeast through to plants, insects, and vertebrates. BAR domain proteins share an N-terminal BAR domain with a high propensity to adopt α-helical structure and engage in coiled-coil interactions with other proteins. BAR domain proteins are implicated in processes as fundamental and diverse as fission of synaptic vesicles, cell polarity, endocytosis, regulation of the actin cytoskeleton, transcriptional repression, cell-cell fusion, signal transduction, apoptosis, secretory vesicle fusion, excitation-contraction coupling, learning and memory, tissue differentiation, ion flux across membranes, and tumor suppression. What has been lacking is a molecular understanding of the role of the BAR domain protein in each process. The three-dimensional structure of the BAR domain has now been determined and valuable insight has been gained in understanding the interactions of BAR domains with membranes. The cellular roles of BAR domain proteins, characterized over the past decade in cells as distinct as yeasts, neurons, and myocytes, can now be understood in terms of a fundamental molecular function of all BAR domain proteins: to sense membrane curvature, to bind GTPases, and to mold a diversity of cellular membranes.

show abstract

Localization of the α1 and α2 subunits of the dihydropyridine receptor and ankyrin in skeletal muscle triads

Cited by 83 publications

References 43 publications

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca ²⁺ channel activity by cAMP-dependent protein kinase

The BAR Domain Proteins: Molding Membranes in Fission, Fusion, and Phagy

Contact Info

Product

Resources

About

Localization of the α1 and α2 subunits of the dihydropyridine receptor and ankyrin in skeletal muscle triads

Cited by 83 publications

References 43 publications

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca 2+ channel activity by cAMP-dependent protein kinase

The BAR Domain Proteins: Molding Membranes in Fission, Fusion, and Phagy

Contact Info

Product

Resources

About

Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca ²⁺ channel activity by cAMP-dependent protein kinase