Severe neuropathy with leaky connexin32 hemichannels

Liang, Grace; Miguel, Marta de; Gómez‐Hernández, Juan M.; Glass, Jonathan D.; Scherer, Steven S.; Mintz, Mark; Barrio, Luis C.; Fischbeck, Kenneth H.

doi:10.1002/ana.20459

Cited by 84 publications

(59 citation statements)

References 18 publications

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“…No currents that could be unequivocally attributed to connexin hemichannels have ever been described in vivo. The examples where genuine connexin hemichannel activity has been demonstrated is limited to mutant connexins (28,37,43) and extreme experimental conditions for wild-type connexins, like membrane potentials exceeding ϩ50 mV (7). But even under such extreme conditions, channel activity was so low that single channel events could be resolved in whole cell patch recordings.…”

Section: Discussionmentioning

confidence: 99%

Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters

Wang¹,

Ma²,

Locovei³

et al. 2007

American Journal of Physiology-Cell Physiology

183

205

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. Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters. Am J Physiol Cell Physiol 293: C1112-C1119, 2007. First published July 27, 2007; doi:10.1152/ajpcell.00097.2007.-Connexin mimetic peptides are widely used to assess the contribution of nonjunctional connexin channels in several processes, including ATP release. These peptides are derived from various connexin sequences and have been shown to attenuate processes downstream of the putative channel activity. Yet so far, no documentation of effects of peptides on connexin channels has been presented. We tested several connexin and pannexin mimetic peptides and observed attenuation of channel currents that is not compatible with sequence specific actions of the peptides. Connexin mimetic peptides inhibited pannexin channel currents but not the currents of the channel formed by connexins from which the sequence was derived. Pannexin mimetic peptides did inhibit pannexin channel currents but also the channels formed by connexin 46. The same pattern of effects was observed for dye transfer, except that the inhibition levels were more pronounced than for the currents. The channel inhibition by peptides shares commonalities with channel effects of polyethylene glycol (PEG), suggesting a steric block as a mechanism. PEG accessibility is in the size range expected for the pore of innexin gap junction channels, consistent with a functional relatedness of innexin and pannexin channels.

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Section: Discussionmentioning

confidence: 99%

Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters

Wang¹,

Ma²,

Locovei³

et al. 2007

American Journal of Physiology-Cell Physiology

183

205

View full text Add to dashboard Cite

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“…altered trafficking resulting in no channels, formation of nonfunctional channels or channels with altered biophysical properties at the plasma membrane) (51,54). However, some CT mutations (F235C, R238H, C280G, and S281x) still form functional gap junction channels, suggesting other mechanisms cause CMTX (51,(55)(56)(57). One possibly, as in the case of F235C, is through altered interactions with protein partners that regulate channel function, such as CaM and SAP97 (57).…”

Section: Proteinmentioning

confidence: 99%

Characterization of the Structure and Intermolecular Interactions between the Connexin 32 Carboxyl-terminal Domain and the Protein Partners Synapse-associated Protein 97 and Calmodulin

Stauch

Kieken

Sorgen

2012

Journal of Biological Chemistry

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Background: SAP97 and CaM play a role in the regulation of connexin 32 (Cx32) gap junctions. Results: SAP97 and CaM affect the same Cx32CT residues, calmodulin induces Cx32CT ␣-helical structure, and Cx32CT mutations that cause X-linked Charcot-Marie-Tooth disease (CMTX) affect the binding of SAP97 and CaM. Conclusion: Cx32-protein partner interactions are important for channel regulation and myelin homeostasis. Significance: Cx32CT mutations may cause CMTX by disrupting the binding of SAP97 and CaM.

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“…Perhaps these mutants do not traffic properly in myelinating Schwann cells, just as certain rhodopsin mutants do not traffic properly in rods (Sung et al, 1994), or perhaps they form channels with abnormal properties (Castro et al, 1999;Abrams et al, 2001;Liang et al, 2005). To address this issue, we used a rat Mpz promoter to drive the expression of the human GJB1 gene (Fig.…”

Section: Generation Of C280g and S281x Transgenic Micementioning

confidence: 99%

“…If these clinical observations are correct, then it will be of interest to establish the basis for both milder and more severe phenotypes. For the F235C mutation, for example, "leaky hemichannels" may be the cause of a more severe phenotype (Liang et al, 2005).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

Huang

Sirkowski²,

Stickney³

et al. 2005

J. Neurosci.

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Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-MarieTooth disease, an inherited demyelinating neuropathy. The C terminus of human Cx32 contains a putative prenylation motif that is conserved in Cx32 orthologs. Using [ 3 H]mevalonolactone ([ 3 H]MVA) incorporation, we demonstrated that wild-type human connexin32 can be prenylated in COS7 cells, in contrast to disease-associated mutations that are predicted to disrupt the prenylation motif. We generated transgenic mice that express these mutants in myelinating Schwann cells. Male mice expressing a transgene were crossed with female Gjb1-null mice; the male offspring were all Gjb1-null, and one-half were transgene positive; in these mice, all Cx32 was derived from expression of the transgene. The mutant human protein was properly localized in myelinating Schwann cells in multiple transgenic lines and did not alter the localization of other components of paranodes and incisures. Finally, both the C280G and the S281x mutants appeared to "rescue" the phenotype of Gjb1-null mice, because transgene-positive male mice had significantly fewer abnormally myelinated axons than did their transgene-negative male littermates. These results indicate that Cx32 is prenylated, but that prenylation is not required for proper trafficking of Cx32 and perhaps not even for certain aspects of its function, in myelinating Schwann cells.

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Severe neuropathy with leaky connexin32 hemichannels

Cited by 84 publications

References 18 publications

Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters

Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters

Characterization of the Structure and Intermolecular Interactions between the Connexin 32 Carboxyl-terminal Domain and the Protein Partners Synapse-associated Protein 97 and Calmodulin

Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

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