Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels

Shuart, Noah Gregory; Haitin, Yoni; Camp, Stacey S.; Black, Kevin D.; Zagotta, William N.

doi:10.1038/ncomms1466

Cited by 86 publications

(99 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The native cone cyclic nucleotide-gated (CNG) channel is composed of three CNGA3 subunits and one CNGB3 subunit, 36 and displays a crucial function in cone phototransduction. [37][38][39] The CNGA3 and CNGB3 subunits are structurally similar, being composed of six transmembrane domains (S1-S6), a pore-forming region, a cyclic nucleotide-binding domain and a C-linker region (Figure 4a).…”

Section: Discussionmentioning

confidence: 99%

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

et al. 2014

View full text Add to dashboard Cite

We assessed a large consanguineous Pakistani family (PKAB157) segregating early onset low vision problems. Funduscopic and electroretinographic evaluation of affected individuals revealed juvenile cone-rod dystrophy (CRD) with maculopathy. Other clinical symptoms included loss of color discrimination, photophobia and nystagmus. Whole-exome sequencing, segregation and haplotype analyses demonstrated that a transition variant (c.955T4C; p.(Cys319Arg)) in CNGA3 co-segregated with the CRD phenotype in family PKAB157. The ability of CNGA3 channel to influx calcium in response to agonist, when expressed either alone or together with the wild-type CNGB3 subunit in HEK293 cells, was completely abolished due to p.Cys319Arg variant. Western blotting and immunolocalization studies suggest that a decreased channel density in the HEK293 cell membrane due to impaired folding and/or trafficking of the CNGA3 protein is the main pathogenic effect of the p.Cys319Arg variant. Mutant alleles of the human cone photoreceptor cyclic nucleotide-gated channel (CNGA3) are frequently associated with achromatopsia. In rare cases, variants in CNGA3 are also associated with cone dystrophy, Leber's congenital amaurosis and oligo cone trichromacy. The identification of predicted p.(Cys319Arg) missense variant in CNGA3 expands the repertoire of the known genetic causes of CRD and phenotypic spectrum of CNGA3 alleles.

show abstract

Section: Discussionmentioning

confidence: 99%

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

et al. 2014

View full text Add to dashboard Cite

show abstract

“…We tentatively assigned CNG-1 and CNG-3 to the CNGA, and CNG-2 and CNG-4 to the CNGB subfamilies on the basis of two sequence criteria. First, a Cterminal leucine zipper-like coiled-coil domain is found in mammalian CNGA but not in CNGB subunits and shown to play a role in correct subunit assembly (Shuart et al, 2011;Zhong et al, 2002). Only TAX-4, CNG-1 and CNG-3 are predicted to contain a C-terminal coiled coil domain with high probability (supplementary material Fig.…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization inC. elegans

Wojtyniak

Brear

O'Halloran

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

SummaryPrimary cilia are ubiquitous sensory organelles that concentrate transmembrane signaling proteins essential for sensing environmental cues. Mislocalization of crucial ciliary signaling proteins, such as the tetrameric cyclic nucleotide-gated (CNG) channels, can lead to cellular dysfunction and disease. Although several cis-and trans-acting factors required for ciliary protein trafficking and localization have been identified, whether these mechanisms act in a protein-and cell-specific manner is largely unknown. Here, we show that CNG channel subunits can be localized to discrete ciliary compartments in individual sensory neurons in C. elegans, suggesting that channel composition is heterogeneous across the cilium. We demonstrate that ciliary localization of CNG channel subunits is interdependent on different channel subunits in specific cells, and identify sequences required for efficient ciliary targeting and localization of the TAX-2 CNGB and TAX-4 CNGA subunits. Using a candidate gene approach, we show that Inversin, transition zone proteins, intraflagellar transport motors and a MYND-domain protein are required to traffic and/or localize CNG channel subunits in both a cell-and channel subunit-specific manner. We further find that TAX-2 and TAX-4 are relatively immobile in specific sensory cilia subcompartments, suggesting that these proteins undergo minimal turnover in these domains in mature cilia. Our results uncover unexpected diversity in the mechanisms that traffic and localize CNG channel subunits to cilia both within and across cell types, highlighting the essential contribution of this process to cellular functions.

show abstract

“…Indeed, the C-termini of three subunits of WT CNGA1 could be linked together by a parallel three-helix coiled-coil domain of a leucine zipper region 30 , and this trimeric structure could be distorted or destroyed in channels formed by two tandems in which one C-terminus is linked to the N-terminus of another subunit. Therefore, we investigated the properties of ion channels obtained when the mutant channels R1Q, R2Q and R3Q were co-expressed in a 1:1 ratio with WT CNGA1 channels (hereafter referred to as R1Q + WT, R2Q + WT and R3Q + WT), where the C-termini are free to form leucine zippers.…”

mentioning

confidence: 99%

Gating of cyclic nucleotide-gated channels is voltage dependent

2012

View full text Add to dashboard Cite

Cyclic nucleotide-gated channels belong to the family of voltage-gated ion channels, but pore opening requires the presence of intracellular cyclic nucleotides. In the presence of a saturating agonist, cyclic nucleotide-gated channel gating is voltage independent and it is not known why cyclic nucleotide-gated channels are voltage-insensitive despite harbouring the s4-type voltage sensor. Here we report that, in the presence of Li + , na + and K + , the gating of wild-type cyclic nucleotide-gated A1 and native cyclic nucleotide-gated channels is voltage independent, whereas their gating is highly voltage-dependent in the presence of Rb + , Cs + and organic cations. mutagenesis experiments show that voltage sensing occurs through a voltage sensor composed of charged/polar residues in the pore and of the s4-type voltage sensor. During evolution, cyclic nucleotide-gated channels lose their voltage-sensing ability when na + or K + permeate so that the vertebrate photoreceptor cyclic nucleotide-gated channels are open at negative voltages, a necessary condition for phototransduction.

show abstract

Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels

Cited by 86 publications

References 55 publications

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization inC. elegans

Gating of cyclic nucleotide-gated channels is voltage dependent

Contact Info

Product

Resources

About