Atrial fibrillation‐linked <i>GJA5</i>/connexin40 mutants impaired gap junctions via different mechanisms

Bai, Donglin

doi:10.1016/j.febslet.2014.02.064

Cited by 35 publications

(21 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Understanding the factors controlling ion permeation can offer new avenues for engineering GJs with enhanced channel function, which can be useful in improving/re‐establishing the GJ function in many disease‐linked connexin mutants (Lee & White, ; Beyer et al . ; Bai, ). Third, the positively charged residue at the same position, G46K, substantially reduced the apparent γ j to 1/10 of the Cx50.…”

Section: Discussionmentioning

confidence: 98%

Charge at the 46th residue of connexin 50 is crucial for the gap‐junctional unitary conductance and transjunctional voltage‐dependent gating

Tong

Aoyama

Tsukihara

et al. 2014

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key pointsr Gap-junction (GJ) channels provide direct intercellular communication and are twice the length of most membrane channels, yet they often have high efficiency in permeation of ions, which is reflected by large unitary channel conductance (γ j ).r To reveal the key factors in determining the γ j of a lens GJ channel, we studied connexin 50 mutant GJ channels, where a negatively or positively charged residue was introduced into a pore-lining domain.r The results indicate that the pore surface electrostatic potential is a dictating factor for the connexin 50 GJ channel γ j .r A change in the local resistance of the channel pore associated with these mutant channels is an important factor for their voltage-dependent gating properties.r The combination of dual patch clamp and homology structure modelling is a powerful approach in revealing molecular mechanisms of GJ gating and ion permeation.Abstract Gap-junction (GJ) channels are twice the length of most membrane channels, yet they often have large unitary channel conductance (γ j ). What factors make this possibly the longest channel so efficient in passing ions are not fully clear. Here we studied the lens connexin (Cx) 50 GJs, which display one of the largest γ j and the most sensitive transjunctional voltage-dependent gating (V j gating) among all GJ channels. Introduction of charged residues into a putative pore-lining domain (the first transmembrane and the first extracellular loop border) drastically altered the apparent γ j . Specifically, G46D and G46E increased the Cx50 γ j from 201 to 256 and 293 pS, respectively and the G46K channel showed an apparent γ j of only 20 pS. G46K also drastically altered V j gating properties in homotypic G46K and heterotypic Cx50/G46K channels, causing an apparent loss of fast V j -dependent gating transitions and leaving only loop gating transitions at the single channel current records. Both macroscopic and single channel currents of heterotypic Cx50/G46K channels showed a prominent rectification. Our homology structural models indicate that the pore surface electrostatic potentials are a dictating factor in determining the γ j . Our data demonstrate, at the whole GJ channel level, a crucial role of the surface charge properties in the first transmembrane/first extracellular border domain in determining the efficiency of ion permeation and the V j gating of Cx50 and possibly other GJ channels.

show abstract

Section: Discussionmentioning

confidence: 98%

Charge at the 46th residue of connexin 50 is crucial for the gap‐junctional unitary conductance and transjunctional voltage‐dependent gating

Tong

Aoyama

Tsukihara

et al. 2014

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Also of interest was the expression of the Gja5, which encodes a gap junction protein CX40 involved in shuttling glutamate, an activator of the N-methyl-D-aspartate (NMDA) glutamate receptor, of which GRIN2A is a subunit (Fig. 5; [58][59][60]). Furthermore, Robo2 and Prokr2 were of interest as both are implicated in neuronal processes and GnRH signaling [41,[61][62][63].…”

Section: Discussionmentioning

confidence: 99%

Purification and Transcriptomic Analysis of Mouse Fetal Leydig Cells Reveals Candidate Genes for Specification of Gonadal Steroidogenic Cells1

McClelland

Bell

Larney

et al. 2015

Biology of Reproduction

View full text Add to dashboard Cite

Male sex determination hinges on the development of testes in the embryo, beginning with the differentiation of Sertoli cells under the influence of the Y-linked gene SRY. Sertoli cells then orchestrate fetal testis formation including the specification of fetal Leydig cells (FLCs) that produce steroid hormones to direct virilization of the XY embryo. As the majority of XY disorders of sex development (DSDs) remain unexplained at the molecular genetic level, we reasoned that genes involved in FLC development might represent an unappreciated source of candidate XY DSD genes. To identify these genes, and to gain a more detailed understanding of the regulatory networks underpinning the specification and differentiation of the FLC population, we developed methods for isolating fetal Sertoli, Leydig, and interstitial cell-enriched subpopulations using an Sf1-eGFP transgenic mouse line. RNA sequencing followed by rigorous bioinformatic filtering identified 84 genes upregulated in FLCs, 704 genes upregulated in nonsteroidogenic interstitial cells, and 1217 genes upregulated in the Sertoli cells at 12.5 days postcoitum. The analysis revealed a trend for expression of components of neuroactive ligand interactions in FLCs and Sertoli cells and identified factors potentially involved in signaling between the Sertoli cells, FLCs, and interstitial cells. We identified 61 genes that were not known previously to be involved in specification or differentiation of FLCs. This dataset provides a platform for exploring the biology of FLCs and understanding the role of these cells in testicular development. In addition, it provides a basis for targeted studies designed to identify causes of idiopathic XY DSD.

show abstract

“…We explored the role of connexin further with molecular studies. GJA5/cx40, a component of the gap junctional channel (27), was detected in both color types of JQ melanocytes ( Fig. 5D and SI Appendix, Fig.…”

Section: Melanoblast/cyte Early Marker-positive Melanocytes Reside Inmentioning

confidence: 99%

Instructive role of melanocytes during pigment pattern formation of the avian skin

Inaba

Jiang

Liang

et al. 2019

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

View full text Add to dashboard Cite

Animal skin pigment patterns are excellent models to study the mechanism of biological self-organization. Theoretical approaches developed mathematical models of pigment patterning and molecular genetics have brought progress; however, the responsible cellular mechanism is not fully understood. One long unsolved controversy is whether the patterning information is autonomously determined by melanocytes or nonautonomously determined from the environment. Here, we transplanted purified melanocytes and demonstrated that melanocytes could form periodic pigment patterns cell autonomously. Results of heterospecific transplantation among quail strains are consistent with this finding. Further, we observe that developing melanocytes directly connect with each other via filopodia to form a network in culture and in vivo. This melanocyte network is reminiscent of zebrafish pigment cell networks, where connexin is implicated in stripe formation via genetic studies. Indeed, we found connexin40 (cx40) present on developing melanocytes in birds. Stripe patterns can form in quail skin explant cultures. Several calcium channel modulators can enhance or suppress pigmentation globally, but a gap junction inhibitor can change stripe patterning. Most interestingly, in ovo, misexpression of dominant negative cx40 expands the black region, while overexpression of cx40 expands the yellow region. Subsequently, melanocytes instruct adjacent dermal cells to express agouti signaling protein (ASIP), the regulatory factor for pigment switching, which promotes pheomelanin production. Thus, we demonstrate Japanese quail melanocytes have an autonomous periodic patterning role during body pigment stripe formation. We also show dermal agouti stripes and how the coupling of melanocytes with dermal cells may confer stable and distinct pigment stripe patterns.Japanese quail | stripe pattern | melanocytes | ASIP | gap junction A nimal skin pigment patterns, such as periodic leopard spots and zebra stripes, represent some of the most amazing phenomena observed in nature, which have fascinated biologists and nonbiologists. The mechanisms of pigment patterning have been studied by mathematical and empirical approaches. Studies on zebrafish stripe patterning have led investigators to propose that the pattern is formed by pigment cell interactions that satisfy a Turing-type model (1,2). Mammalian genetic studies performed on horses, zebras, cheetahs, and chipmunks have identified some of the molecules involved in this process (3-5). Although theoretical models and the genetic backgrounds in the pigment patterning are well studied, how the pigment-related genes control the cell-cell interactions that generate the pigment pattern is largely unknown. Avian species present an excellent model system to answer these questions because of their extraordinarily diverse micropigment patterns within feathers (6) and embryonic manipulability that allows analyses of cell-cell interactions leading to macropigment patterning throughout the body. Japanese quail (JQ), a m...

show abstract

Atrial fibrillation‐linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms

Cited by 35 publications

References 110 publications

Charge at the 46th residue of connexin 50 is crucial for the gap‐junctional unitary conductance and transjunctional voltage‐dependent gating

Charge at the 46th residue of connexin 50 is crucial for the gap‐junctional unitary conductance and transjunctional voltage‐dependent gating

Purification and Transcriptomic Analysis of Mouse Fetal Leydig Cells Reveals Candidate Genes for Specification of Gonadal Steroidogenic Cells1

Instructive role of melanocytes during pigment pattern formation of the avian skin

Contact Info

Product

Resources

About