A 240 kDa protein represents the complete β subunit of the cyclic nucleotide-gated channel from rod photoreceptor

̈rschen, Heinz Gerd Ko; Illing, Michelle; Seifer, Reinhard; Sesti, Federico; Williams, Andrew H; Gotzes, S; Colville, Caroline A.; Müller, Frank; Dosé, Andréa C.; Godde, Matthias; Molday, Laurie L.; Kaupp, U. Benjamin; Molday, Robert S.

doi:10.1016/0896-6273(95)90151-5

Cited by 231 publications

(279 citation statements)

References 31 publications

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“…A generally assumed uniform distribution of PDE6 on the disc membrane clearly contrasts with the known interaction of PDE6 with GARP2 (glutamic acid-rich protein-2) (30,32). GARP2 is an abundant soluble protein variant of the GARP region of the cGMP-gated channel ␤-subunit (30,33). In ROS, GARP2 is confined to the rim region and incisures of discs, apparently due to its interaction with peripherin-2 oligomers (30,34).…”

Section: Discussionmentioning

confidence: 80%

Characterization of Human Cone Phosphodiesterase-6 Ectopically Expressed in Xenopus laevis Rods

Muradov

Boyd

Haeri

et al. 2009

Journal of Biological Chemistry

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PDE6 (phosphodiesterase-6) is the effector molecule in the vertebrate phototransduction cascade. Progress in understanding the structure and function of PDE6 has been hindered by lack of an expression system of the enzyme. Here we report ectopic expression and analysis of compartmentalization and membrane dynamics of the enhanced green fluorescent protein (EGFP) fusion protein of human cone PDE6C in rods of transgenic Xenopus laevis. EGFP-PDE6C is correctly targeted to the rod outer segments in transgenic Xenopus, where it displayed a characteristic striated pattern of EGFP fluorescence. Immunofluorescence labeling indicated significant and light-independent co-localization of EGFP-PDE6C with the disc rim marker peripherin-2 and endogenous frog PDE6. The diffusion of EGFP-PDE6C on disc membranes investigated with fluorescence recovery after photobleaching was markedly slower than theoretically predicted. The enzymatic characteristics of immunoprecipitated recombinant PDE6C were similar to known properties of the native bovine PDE6C. PDE6C was potently inhibited by the cone-and rod-specific PDE6 ␥-subunits. Thus, transgenic Xenopus laevis is a unique expression system for PDE6 well suited for analysis of the mechanisms of visual diseases linked to PDE6 mutations.Phosphodiesterases of cyclic nucleotides (PDEs) 2 are essential enzymes controlling cellular levels of cAMP and cGMP. Eleven families of PDEs have been identified in mammals on the grounds of sequence homology, substrate selectivity, and regulation (1). Photoreceptor-specific PDEs in rods and cones comprise the sixth PDE family (PDE6) and serve as the effector enzymes in the vertebrate phototransduction cascade (1-5). Rod PDE6 is composed of homologous catalytic ␣-subunit (PDE6A) and ␤-subunit (PDE6B) and two copies of a small inhibitory ␥-subunit (P␥) (3). Cone PDE6 is a catalytic dimer of two identical ␣Ј-subunits (PDE6C) (3). A cone-specific inhibitory P␥-subunit is highly homologous to the rod P␥ (6). In rod photoreceptors, PDE6 is located in the specialized compartments called rod outer segments (ROS), where it associates with disc membranes. The membrane attachment of PDE6 is mediated by farnesylation of the PDE6A C terminus and geranylgeranylation of the PDE6B C terminus (7). In cones, geranylgeranylated PDE6C resides on infoldings of the cone outer segment plasma membrane (8). Following photoexcitation of rod or cone photoreceptor cells, PDE6 is activated by the GTPbound transducin ␣-subunit (G␣ t GTP) that relieves the P␥ inhibition of the enzyme. cGMP hydrolysis by active PDE6 leads to a cellular response due to a closure of cGMP-gated channels in the photoreceptor plasma membrane (2-5).Although PDE6 plays a prominent role in vertebrate vision, the structure-function relationships of PDE6 are poorly understood in comparison with other key phototransduction proteins. The lack of an expression system for PDE6 has become a major impediment for PDE6 research. Importantly, an expression system for PDE6 is required to elucidate the mechanisms of visua...

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Section: Discussionmentioning

confidence: 80%

Characterization of Human Cone Phosphodiesterase-6 Ectopically Expressed in Xenopus laevis Rods

Muradov

Boyd

Haeri

et al. 2009

Journal of Biological Chemistry

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“…The high sensitivity of the native rod channel to L-cisdiltiazem is now known to be conferred by a [3-subunit coupled to the ~-subunit [19,22]. The same may be true for the native cone channel [25].…”

Section: Vk Yu Et Al/febs Letters 393 (1996) 211~15mentioning

confidence: 97%

“…Ca2+-calmodulin strongly inhibits the native olfactory channel by binding to its ot-subunit [32,33], and also inhibits the native rod channel by binding to its [~-subunit [30,31,34,22]. On the other hand, the native cone channel, at least from catfish [35], is not modulated by Ca2+-calmodulin.…”

Section: Vk Yu Et Al/febs Letters 393 (1996) 211~15mentioning

confidence: 99%

“…Finally, both the human and bovine [18,25] channel homologs showed little sensitivity to L-Cis-diltiazem, unlike the native cone channel in fish [42]. This difference suggests the presence of a ]3-subunit in the native cone channel complex that is responsible for the high sensitivity to t-cis-diltiazem [25], as is the case for the native rod channel [19,22]. Whether a cone [3-subunit distinct from that in rods exists remains to be determined.…”

Section: Vk Yu Et Al/febs Letters 393 (1996) 211~15mentioning

confidence: 99%

“…For the olfactory channel, this inhibition involves direct binding of Ca2+-calmodulin to the c~-subunit [33] whereas the inhibition of the rod channel depends on Ca2+-calmodulin binding to the [3-subunit [34,22]. So far, the effect of Ca 2+-calmodulin on the native cone channel has only been studied in fish, and no modulation was found [35].…”

Section: Introductionmentioning

confidence: 99%

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Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide‐gated ion channel of retinal cone photoreceptors

Grunwald

Yau

1996

FEBS Letters

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We have cloned from human retina a cyclic nucleotide-gated (CNG) ion channel that is distinct from the one found in rod photoreceptors. This channel protein is highly homologous to the CNG channel that recently has been cloned from bovine testis and kidney and has been shown to be present in retinal cone photoreceptors. When expressed in human embryonic kidney cells, the protein forms functional ion channels with properties broadly similar to those described for the cloned bovine channel. The gene for this channel resides on chromosome 2.

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Olfactory Dysfunction in Patients WithCNGB1-Associated Retinitis Pigmentosa

et al. 2018

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etinitis pigmentosa (RP) (OMIM 26800) is a genetically heterogeneous disease characterized by poor night vision and loss of peripheral visual field owing to a decline in rod-dependent vision. Later in the disease course, cones and thus the central visual field and visual acuity may also be affected. Retinitis pigmentosa is caused by mutations in genes coding for proteins involved in photoreceptor function, structure, and/or maintenance. When the gene product is expressed exclusively in the retina or when its lack is compensated for in other tissues, the disease remains restricted to the retina. However, significant expression of the gene product in other organs may result in syndromic RP with morphological and/or functional consequences affecting other organs. Cyclic nucleotide-gated (CNG) channels are key components for signal transduction in photoreceptors and olfactory sensory neurons (OSNs). 1 They function as tetramers composed of α and β subunits. Specific types of heterotetramers are expressed in different sensory cells. For example, the rod CNG channel consists of 3 CNGA1 subunits and 1 CNGB1 subunit, 2 the cone CNG channel consists of 3 CNGA3 subunits and 1 CNGB3 subunit, 3,4 and the CNG channel of OSNs (olfCNG) consists of 2 CNGA2 subunits, 1 CNGA4 subunit, and 1 CNGB1b subunit. 5 Therefore, only the CNGB1 subunit is involved in both photoreceptor and olfactory signal transduction. In contrast to most CNGA subunits that are regarded as main subunits IMPORTANCE Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. OBJECTIVE To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. DESIGN, SETTING, AND PARTICIPANTS This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. MAIN OUTCOMES AND MEASURES Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. RESULTS Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050...

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A 240 kDa protein represents the complete β subunit of the cyclic nucleotide-gated channel from rod photoreceptor

Cited by 231 publications

References 31 publications

Characterization of Human Cone Phosphodiesterase-6 Ectopically Expressed in Xenopus laevis Rods

Characterization of Human Cone Phosphodiesterase-6 Ectopically Expressed in Xenopus laevis Rods

Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide‐gated ion channel of retinal cone photoreceptors

Olfactory Dysfunction in Patients WithCNGB1-Associated Retinitis Pigmentosa

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