Disease relevance of CNGA1

• A mutation in a cyclic nucleotide-gated channel (CNGA1) is associated with retinitis pigmentosa (RP), a common, inherited eye disease [1].
• S4 must be functionally important because its natural mutation in cone photoreceptor CNG channels is associated with achromatopsia, a human autosomal inherited loss of cone function [2].
• The ligand-binding domains of cyclic nucleotide-gated (CNG) channels show sequence homology to corresponding region(s) of the Escherichia coli catabolite gene-activator protein (CAP) and to the regulatory subunit of cAMP-dependent or cGMP-dependent protein kinases [3].
• CONCLUSIONS: Our results raise the possibility that retinoids, such as all-trans C22 aldehyde, that inhibit CNG channels without affecting the transduction cascade, may be useful in treating degenerative retinal diseases in which either the cGMP concentration is elevated or the CNG channels are hypersensitive to cGMP [4].

Psychiatry related information on CNGA1

• Cyclic nucleotide-gated (CNG) channels have been characterized as important factors involved in physiological processes including sensory reception for vision and olfaction [5].

High impact information on CNGA1

• Here we combine the high resolution of single-channel recording with the use of a photoaffinity analogue of cGMP that tethers cGMP moieties covalently to their binding sites to show single retinal CNG channels can be effectively locked in four distinct ligand-bound states [6].
• The cloning of the gene coding for a rod photoreceptor channel (Kaupp et al 1989) and the subsequent cloning of related genes from olfactory neurons (Dhallan et al 1990, Ludwig et al 1990, Goulding et al 1992) has sparked much progress over the past several years in elucidating the structural bases for the function of the CNG channels [7].
• Cyclic nucleotide-gated (CNG) channels play important roles in both visual (Yau & Baylor 1989) and olfactory (Zufall et al 1994) signal transduction [7].
• Cyclic nucleotide-gated (CNG) channels serve as downstream targets of signalling pathways in vertebrate photoreceptor cells and olfactory sensory neurons (see ref. 1 for review) [8].
• Ca2+ ions that enter through CNG channels intimately control these signalling pathways by regulating synthesis or hydrolysis of cyclic nucleotides, and by decreasing ligand sensitivity of CNG channels [8].

Chemical compound and disease context of CNGA1

• PURPOSE: To determine whether inhibition of cyclic nucleotide-gated (CNG) ion channels by retinoids might be useful in treating degenerative retinal diseases in which either the CNG channels are hypersensitive to 3',5'-cyclic guanosine monophosphate (cGMP) or the photoreceptor cGMP concentration is elevated [4].

Biological context of CNGA1

• The cyclic nucleotide-gated (CNG) ion channels, with their Ca(2+) permeability, high sensitivity to changes in cytosolic cGMP, rapid gating kinetics, and Ca(2+)-calmodulin modulation, are beautifully optimized for their role in light detection [9].
• Unlike CNGA1, CNGB1 does not exhibit activity dependence of modulation by tyrosine phosphorylation [10].
• Its deduced amino acid sequence is 60% and 62% identical with the CNG-channel proteins from bovine rod outer segment and bovine olfactory epithelium, respectively [11].
• The cyclic nucleotide-gated (CNG) channel in retinal rods converts the light-regulated intracellular cGMP concentration to various levels of membrane potential [12].
• Here, we report that a point mutation at position 204 in the S2-S3 loop of Rolf and a mouse CNG channel (Molf) found in olfactory epithelium and heart, increased DAG sensitivity to that of the Brod channel [13].

Anatomical context of CNGA1

• Subunit stoichiometry of the CNG channel of rod photoreceptors [14].
• Cyclic nucleotide-gated (CNG) ion channels, underlying sensory transduction in vertebrate photoreceptors and olfactory sensory neurons, require cyclic nucleotides to open [15].
• Expression of mutant (CNGA1-RP) homomeric channels in Xenopus oocytes revealed no measurable differences compared to wild-type CNGA1 homomers [1].
• Sensory transduction in vertebrate photoreceptors and olfactory sensory neurons is mediated by cyclic nucleotide-gated (CNG) channels that conduct mono- and divalent cations [16].
• Cloned CNG channels from photoreceptors and olfactory sensory neurons profoundly differ in their relative Ca2+ permeability, their blockage by external divalent cations, and the fraction of current carried by Ca2+ [16].

Associations of CNGA1 with chemical compounds

• We previously noted that dequalinium is a high-affinity blocker of CNGA1 channels from the intracellular side, with little or no state dependence at 0 mV [17].
• The tetracaine analogues described here have apparent affinities for CNGA1 channels that vary over nearly 8 orders of magnitude [18].
• Replacement of either Y498 of CNGA1 or Y1097 of CNGB1 with phenylalanine reduces modulation, and removal of both tyrosines eliminates modulation [10].
• A CNG1 channel pore was probed using site-directed cysteine substitution to elucidate conformational changes associated with channel opening [19].
• To determine the subunit stoichiometry of CNG ion channels, we have coexpressed the 30 pS conductance bovine retinal channel (RET) with an 85 pS conductance chimeric retinal channel containing the catfish olfactory channel P region (RO133) [20].

Other interactions of CNGA1

• Thus, disruption of a regulatory interaction by mutation in CNGA1 exposed a region of CNGB1 that disrupted surface expression of heteromeric CNGA1-RP/CNGB1 channels, accounting for this instance of RP [1].
• Here we examined block by dequalinium at a broad range of voltages in both CNGA1 and CNGA2 channels [17].
• Previous studies on heterologously expressed rod CNG channels show that a specific tyrosine in the CNGA1 subunit (Y498) is required for modulation by protein tyrosine phosphatases, protein tyrosine kinases and IGF-1 [10].

Analytical, diagnostic and therapeutic context of CNGA1

• We have purified the CNG channel from bovine retina and have studied it using electron microscopy and image processing [21].
• Confocal microscopy in conjunction with the Ca2+ indicator Fluo-3 shows that the CNG channels serve as a Ca2+ entry pathway that responds more sensitively to cGMP than to cAMP [22].
• Sequences specific for cyclic nucleotide-gated channels (CNG channels) have been amplified by PCR from cDNA of heart, aorta, sino-atrial node, cerebellum, C-cells and kidney [23].
• Southern blot analysis with human genomic DNA revealed specific patterns of hybridization with probes derived from the different CNG channel types indicating that they are encoded by distinct genes [24].
• The complete amino acid sequence of a CNG channel from rabbit aorta has been deduced by cloning and sequence analysis of the cDNA [23].

References