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CNGA3

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Target not currently curated in GtoImmuPdb

Target id: 396

Nomenclature: CNGA3

Family: Cyclic nucleotide-regulated channels (CNG)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 694 2q11.2 CNGA3 cyclic nucleotide gated channel subunit alpha 3 26,28
Mouse 3 1 631 1 B Cnga3 cyclic nucleotide gated channel alpha 3 7
Rat 6 1 611 9q21 Cnga3 cyclic nucleotide gated channel subunit alpha 3 16
Previous and Unofficial Names Click here for help
CCNC1 | ACHM2 | CNCG3 | CCNCa
Database Links Click here for help
Alphafold Q16281 (Hs), Q9JJZ8 (Mm)
CATH/Gene3D 2.60.120.10
Ensembl Gene ENSG00000144191 (Hs), ENSMUSG00000026114 (Mm), ENSRNOG00000017582 (Rn)
Entrez Gene 1261 (Hs), 12790 (Mm), 85257 (Rn)
Human Protein Atlas ENSG00000144191 (Hs)
KEGG Gene hsa:1261 (Hs), mmu:12790 (Mm), rno:85257 (Rn)
OMIM 600053 (Hs)
Orphanet ORPHA120671 (Hs)
Pharos Q16281 (Hs)
RefSeq Nucleotide NM_001298 (Hs), NM_009918 (Mm), NM_053495 (Rn)
RefSeq Protein NP_001073347 (Hs), NP_034048 (Mm), NP_445947 (Rn)
UniProtKB Q16281 (Hs), Q9JJZ8 (Mm)
Wikipedia CNGA3 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
CNGB3 5,13
EMILIN1 21
CDH23 22
MyosinVIIa 22
Functional Characteristics Click here for help
γ = 40 pS
PCa/PNa = 10.9
Ion Selectivity and Conductance Click here for help
Species:  None
Rank order:  Ca2+ > Rb+ = Na+ = K+ > Li+ > Cs+ [28.0 - 41.0 pS]
References:  3,12,19,23,28
Activators (Human)
cyclic GMP (EC50 ~ 30 μM) >> cyclic AMP

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Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
cyclic GMP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Agonist 5.5 pKd - -80.0 – 80.0 12
⤷ pKd 5.5 [12]
Holding voltage: -80.0 – 80.0 mV
cyclic GMP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.7 – 5.6 pKd - -60.0 – 80.0 18,26,28
⤷ pKd 4.7 – 5.6 [18,26,28]
Holding voltage: -60.0 – 80.0 mV
cyclic AMP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Agonist 3.6 pKd - -80.0 12
⤷ pKd 3.6 [12]
Holding voltage: -80.0 mV
cyclic AMP Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 2.9 pKd - -60.0 – 80.0 18,28
⤷ pKd 2.9 [18,28]
Holding voltage: -60.0 – 80.0 mV
View species-specific activator tables
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
L-(cis)-diltiazem Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - - - - -
⤷ high affinity binding requires presence of CNGB subunits
Tissue Distribution Click here for help
Retina.
Species:  Human
Technique:  Northern Blot
References:  26
Cone photoreceptors.
Species:  Human
Technique:  Immunohistochemistry
References:  26
Cone photoreceptors.
Species:  Mouse
Technique:  Immunohistochemistry
References:  3,7
Cone photoreceptors, subset of olfactory sensory neurons, taste buds.
Species:  Rat
Technique:  Immunohistochemistry
References:  14-15
Cochlea
Species:  Rat
Technique:  Immunohistochemistry
References:  21
Physiological Functions Click here for help
This subunit assembles with CNGB3 to form the native cone CNG channel. This channel mediates the Na+/Ca2+ influx that depolarises cone photoreceptors in the dark ("dark current").
Species:  Human
Tissue:  Retina.
References:  11,26
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cnga3tm1Biel|Gnat1tm1Clma|Opn4tm1Yau Cnga3tm1Biel/Cnga3tm1Biel,Gnat1tm1Clma/Gnat1tm1Clma,Opn4tm1Yau/Opn4tm1Yau
involves: 129 * C57BL/6		 MGI:1341818  MGI:1353425  MGI:95778  MP:0001502 abnormal circadian rhythm PMID: 12808468 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1341818  MP:0005551 abnormal eye electrophysiology PMID: 10377453 
Cnga3tm1Biel|Rpe65tm1Tmr Cnga3tm1Biel/Cnga3tm1Biel,Rpe65tm1Tmr/Rpe65tm1Tmr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1341818  MGI:98001  MP:0005551 abnormal eye electrophysiology PMID: 11528395 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0005551 abnormal eye electrophysiology PMID: 15161873 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1341818  MP:0005253 abnormal eye physiology PMID: 10377453 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0006068 abnormal horizontal cell morphology PMID: 15161873 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ		 MGI:1341818  MP:0009943 abnormal olfactory bulb periglomerular cell morphology PMID: 17724338 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ		 MGI:1341818  MP:0001983 abnormal olfactory system physiology PMID: 17724338 
Cnga3tm1Biel|Gnat1tm1Clma|Opn4tm1Yau Cnga3tm1Biel/Cnga3tm1Biel,Gnat1tm1Clma/Gnat1tm1Clma,Opn4tm1Yau/Opn4tm1Yau
involves: 129 * C57BL/6		 MGI:1341818  MGI:1353425  MGI:95778  MP:0002638 abnormal pupillary reflex PMID: 12808468 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1341818  MP:0008449 abnormal retinal cone cell outer segment morphology PMID: 10377453 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0006069 abnormal retinal neuronal layer morphology PMID: 15161873 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0006074 abnormal retinal rod bipolar cell morphology PMID: 15161873 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0001005 abnormal retinal rod cell morphology PMID: 15161873 
Cnga3tm1Biel Cnga3tm1Biel/Cnga3tm1Biel
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1341818  MP:0001327 decreased retinal photoreceptor cell number PMID: 10377453 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0001327 decreased retinal photoreceptor cell number PMID: 15161873 
Cnga3tm1Biel|Gnat1tm1Clma|Opn4tm1Yau Cnga3tm1Biel/Cnga3tm1Biel,Gnat1tm1Clma/Gnat1tm1Clma,Opn4tm1Yau/Opn4tm1Yau
involves: 129 * C57BL/6		 MGI:1341818  MGI:1353425  MGI:95778  MP:0002003 miotic pupils PMID: 12808468 
Cnga3tm1Biel|Rhotm1Phm Cnga3tm1Biel/Cnga3tm1Biel,Rhotm1Phm/Rhotm1Phm
involves: C57BL/6		 MGI:1341818  MGI:97914  MP:0008450 retinal photoreceptor degeneration PMID: 15161873 
Cnga3tm1Biel|Gnat1tm1Clma|Opn4tm1Yau Cnga3tm1Biel/Cnga3tm1Biel,Gnat1tm1Clma/Gnat1tm1Clma,Opn4tm1Yau/Opn4tm1Yau
involves: 129 * C57BL/6		 MGI:1341818  MGI:1353425  MGI:95778  MP:0002563 shortened circadian period PMID: 12808468 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Achromatopsia 2; ACHM2
Synonyms: Achromatopsia [Orphanet: ORPHA49382] [Disease Ontology: DOID:13911]
Disease Ontology: DOID:13911
OMIM: 216900
Orphanet: ORPHA49382
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Insertion Human G49fs 148insG Exon 2 25
Frameshift: Insertion Human V451fs 1350insG Exon 7 25
Frameshift: Insertion Human I482fs 1443insC Occurs as a compound heterozygous mutation with R569H 8
In-frame deletion Human I312del 934-936delATC Exon 7 25
Missense Human D162V 25
Missense Human P163L 11,25
Missense Human Y181C 25
Missense Human N182Y 25
Missense Human L186F 25
Missense Human C191Y 25
Missense Human E194K 25
Missense Human R223W 8,17,25,27
Missense Human T224R 25
Missense Human T224R 27
Missense Human E228K 20
Missense Human F249S 17
Missense Human D252N 10
Missense Human D260N 25
Missense Human Y263D 17
Missense Human G267D 25
Missense Human R274S 2
Missense Human R277H 25
Missense Human R277C 17,25
Missense Human R283W 1,11,25
Missense Human R283Q 11,25
Missense Human T291R 11,25
Missense Human S341P 17,25
Missense Human T369S 25
Missense Human P372S 25
Missense Human F380S 25
Missense Human G397V 1
Missense Human S401P 17
Missense Human M406T 25
Missense Human R410W 17,25
Missense Human R427C 17,25
Missense Human L433W 10
Missense Human R436W 6,8,17,25
Missense Human R439W 20
Missense Human A469T 20
Missense Human N471S 25
Missense Human D485V 25
Missense Human C510S 25
Missense Human G513E 25
Missense Human G516E 25
Missense Human I522T 25
Missense Human G525D 25
Missense Human V529M 11,17,25
Missense Human F547L 8,11,25
Missense Human G548R 8
Missense Human G557R 11,25
Missense Human R563C 10
Missense Human R563H 25
Missense Human T565M 17,25
Missense Human R569H 1706G>A Occurs as a compound heterozygous mutation with I482fs 8,25
Missense Human Y573C 25
Missense Human E590K 17
Missense Human E593K 25
Missense Human A621E 27
Missense Human L633P 6
Nonsense Human R23X 67C>T 8
Nonsense Human Q196X 586C>T 8
Nonsense Human R221X 661C>T 8
Nonsense Human W316X 947G>A 25
Nonsense Human E344X c.1030G>T exon 7 17
Nonsense Human W440X 1320G>A exon 7 25
Nonsense Human Q537X 1609C>T exon 7 25
Nonsense Human Q655X 1963C>T exon 7 25
General Comments
CNGA3 is also expressed in bovine sperm [4,9,23-24]. The physiological relevance in this cell type is unclear. Mice lacking the CNGA3 subunit show normal fertility [3].

References

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1. Ahuja Y, Kohl S, Traboulsi EI. (2008) CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis, 14: 1293-7. [PMID:18636117]

2. Azam M, Collin RW, Shah ST, Shah AA, Khan MI, Hussain A, Sadeque A, Strom TM, Thiadens AA, Roosing S et al.. (2010) Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia. Mol Vis, 16: 774-81. [PMID:20454696]

3. Biel M, Seeliger M, Pfeifer A, Kohler K, Gerstner A, Ludwig A, Jaissle G, Fauser S, Zrenner E, Hofmann F. (1999) Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc Natl Acad Sci USA, 96 (13): 7553-7. [PMID:10377453]

4. Biel M, Zong X, Distler M, Bosse E, Klugbauer N, Murakami M, Flockerzi V, Hofmann F. (1994) Another member of the cyclic nucleotide-gated channel family, expressed in testis, kidney, and heart. Proc Natl Acad Sci USA, 91 (9): 3505-9. [PMID:8170936]

5. Gerstner A, Zong X, Hofmann F, Biel M. (2000) Molecular cloning and functional characterization of a new modulatory cyclic nucleotide-gated channel subunit from mouse retina. J Neurosci, 20 (4): 1324-32. [PMID:10662822]

6. Goto-Omoto S, Hayashi T, Gekka T, Kubo A, Takeuchi T, Kitahara K. (2006) Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia. Vis Neurosci, 23 (3-4): 395-402. [PMID:16961972]

7. Hirano AA, Hack I, Wässle H, Duvoisin RM. (2000) Cloning and immunocytochemical localization of a cyclic nucleotide-gated channel alpha-subunit to all cone photoreceptors in the mouse retina. J Comp Neurol, 421 (1): 80-94. [PMID:10813773]

8. Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. (2004) Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet, 41 (2): e20. [PMID:14757870]

9. Kaupp UB, Seifert R. (2002) Cyclic nucleotide-gated ion channels. Physiol Rev, 82 (3): 769-824. [PMID:12087135]

10. Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B. (2008) Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). Eur J Neurosci, 27 (9): 2391-401. [PMID:18445228]

11. Kohl S, Marx T, Giddings I, Jägle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. (1998) Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet, 19 (3): 257-9. [PMID:9662398]

12. Lee HM, Park YS, Kim W, Park CS. (2001) Electrophysiological characteristics of rat gustatory cyclic nucleotide--gated channel expressed in Xenopus oocytes. J Neurophysiol, 85 (6): 2335-49. [PMID:11387380]

13. Matveev AV, Quiambao AB, Browning Fitzgerald J, Ding XQ. (2008) Native cone photoreceptor cyclic nucleotide-gated channel is a heterotetrameric complex comprising both CNGA3 and CNGB3: a study using the cone-dominant retina of Nrl-/- mice. J Neurochem, 106 (5): 2042-55. [PMID:18665891]

14. Meyer MR, Angele A, Kremmer E, Kaupp UB, Muller F. (2000) A cGMP-signaling pathway in a subset of olfactory sensory neurons. Proc Natl Acad Sci USA, 97 (19): 10595-600. [PMID:10984544]

15. Misaka T, Ishimaru Y, Iwabuchi K, Kusakabe Y, Arai S, Emori Y, Abe K. (1999) A gustatory cyclic nucleotide-gated channels CNGgust, is expressed in the retina. Neuroreport, 10 (4): 743-6. [PMID:10208541]

16. Misaka T, Kusakabe Y, Emori Y, Gonoi T, Arai S, Abe K. (1997) Taste buds have a cyclic nucleotide-activated channel, CNGgust. J Biol Chem, 272 (36): 22623-9. [PMID:9278419]

17. Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. (2005) Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat, 25 (3): 248-58. [PMID:15712225]

18. Peng C, Rich ED, Thor CA, Varnum MD. (2003) Functionally important calmodulin-binding sites in both NH2- and COOH-terminal regions of the cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit. J Biol Chem, 278 (27): 24617-23. [PMID:12730238]

19. Peng C, Rich ED, Varnum MD. (2003) Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. J Biol Chem, 278 (36): 34533-40. [PMID:12815043]

20. Reuter P, Koeppen K, Ladewig T, Kohl S, Baumann B, Wissinger B, Achromatopsia Clinical Study Group. (2008) Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. Hum Mutat, 29 (10): 1228-36. [PMID:18521937]

21. Selvakumar D, Drescher MJ, Dowdall JR, Khan KM, Hatfield JS, Ramakrishnan NA, Drescher DG. (2012) CNGA3 is expressed in inner ear hair cells and binds to an intracellular C-terminus domain of EMILIN1. Biochem J, 443 (2): 463-76. [PMID:22248097]

22. Selvakumar D, Drescher MJ, Drescher DG. (2013) Cyclic nucleotide-gated channel α-3 (CNGA3) interacts with stereocilia tip-link cadherin 23 + exon 68 or alternatively with myosin VIIa, two proteins required for hair cell mechanotransduction. J Biol Chem, 288 (10): 7215-29. [PMID:23329832]

23. Weyand I, Godde M, Frings S, Weiner J, Müller F, Altenhofen W, Hatt H, Kaupp UB. (1994) Cloning and functional expression of a cyclic-nucleotide-gated channel from mammalian sperm. Nature, 368 (6474): 859-63. [PMID:7512693]

24. Wiesner B, Weiner J, Middendorff R, Hagen V, Kaupp UB, Weyand I. (1998) Cyclic nucleotide-gated channels on the flagellum control Ca2+ entry into sperm. J Cell Biol, 142 (2): 473-84. [PMID:9679145]

25. Wissinger B, Gamer D, Jägle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. (2001) CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet, 69 (4): 722-37. [PMID:11536077]

26. Wissinger B, Müller F, Weyand I, Schuffenhauer S, Thanos S, Kaupp UB, Zrenner E. (1997) Cloning, chromosomal localization and functional expression of the gene encoding the alpha-subunit of the cGMP-gated channel in human cone photoreceptors. Eur J Neurosci, 9 (12): 2512-21. [PMID:9517456]

27. Wiszniewski W, Lewis RA, Lupski JR. (2007) Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet, 121 (3-4): 433-9. [PMID:17265047]

28. Yu WP, Grunwald ME, Yau KW. (1996) Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide-gated ion channel of retinal cone photoreceptors. FEBS Lett, 393 (2-3): 211-5. [PMID:8814292]

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