Ankyrin-3 (ANK-3), also known as ankyrin-G, is a
protein from
ankyrin family that in humans is encoded by the ANK3gene.[5][6]
Function
The
protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins
ANK1 and
ANK2, and was originally found at the
axonal initial segment and
nodes of Ranvier of
neurons in the central and peripheral nervous systems. Alternatively spliced variants may be expressed in other tissues. Although multiple transcript variants encoding several different isoforms have been found for this gene, the full-length nature of only two have been characterized.[5]
Within the nervous system, ankyrin-G is specifically localized to the
neuromuscular junction, the axon initial segment and the
Nodes of Ranvier.[7] Within the nodes of Ranvier where
action potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner to
neurofascin and voltage-gated
sodium channels.[8] The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gated
sodium channels at the
axon hillock and for
action potential firing.[9][10]
Disease linkage
The ANK3 protein associates with the cardiac sodium channel
Nav1.5 (SCN5A). Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in
cardiomyocytes. A mutation in the Nav1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Nav1.5 in cardiomyocytes resulting in
Brugada syndrome, a type of cardiac
arrhythmia.[11]
The protein encoded by the ANK3 gene is a member of the
ankyrin family of proteins that link the integral membrane proteins to the underlying
spectrin-
actincytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation.[5]
^Kapfhamer D, Miller DE, Lambert S, Bennett V, Glover TW, Burmeister M (May 1995). "Chromosomal localization of the ankyrin-G gene (ANK3/Ank3) to human 10q21 and mouse 10". Genomics. 27 (1): 189–91.
doi:
10.1006/geno.1995.1023.
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^Iqbal, Zafar; Vandeweyer, Geert; van der Voet, Monique; Waryah, Ali Muhammad; Zahoor, Muhammad Yasir; Besseling, Judith A.; Roca, Laura Tomas; Vulto-van Silfhout, Anneke T.; Nijhof, Bonnie; Kramer, Jamie M.; Van der Aa, Nathalie; Ansar, Muhammad; Peeters, Hilde; Helsmoortel, Celine; Gilissen, Christian; Vissers, Lisenka; Veltman, Joris A.; de Brouwer, Arjan P. M.; Kooy, R. Frank; Riazuddin, Sheikh; Schenck, Annette; van Bokhoven, Hans; Rooms, Liesbeth (2013).
"Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders". Human Molecular Genetics. 22 (10): 1960–1970.
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Weimer JM, Chattopadhyay S, Custer AW, Pearce DA (2005). "Elevation of Hook1 in a disease model of Batten disease does not affect a novel interaction between Ankyrin G and Hook1". Biochem. Biophys. Res. Commun. 330 (4): 1176–81.
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Shirahata E, Iwasaki H, Takagi M, et al. (2006). "Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6". J. Neurophysiol. 96 (3): 1347–57.
doi:
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Morgan AR, Turic D, Jehu L, et al. (2007). "Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (6): 762–70.
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