ANK3

Ankyrin-3 (ANK-3), also known as ankyrin-G, is a is_associated_with::protein from is_associated_with::ankyrin family that in humans is encoded by the ANK3 is_associated_with::gene.

Function
The is_associated_with::protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins is_associated_with::ANK1 and is_associated_with::ANK2, and was originally found at the axonal initial segment and is_associated_with::nodes of Ranvier of is_associated_with::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.

Within the nervous system, ankyrin-G is specifically localized to the is_associated_with::neuromuscular junction, the axon initial segment and the is_associated_with::Nodes of Ranvier. Within the nodes of Ranvier where is_associated_with::action potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner to is_associated_with::neurofascin and voltage-gated is_associated_with::sodium channels. The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gated is_associated_with::sodium channels at the is_associated_with::axon hillock and for is_associated_with::action potential firing.

Disease linkage
The ANK3 protein associates with the cardiac sodium channel Nav1.5. Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in is_associated_with::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 is_associated_with::Brugada syndrome, a type of cardiac is_associated_with::arrhythmia.

Other mutations in the ANK3 gene may be involved in the is_associated_with::bipolar disorder and is_associated_with::intellectual disability.

Ankyrin family
The protein encoded by the ANK3 gene is a member of the is_associated_with::ankyrin family of proteins that link the integral membrane proteins to the underlying is_associated_with::spectrin-is_associated_with::actin is_associated_with::cytoskeleton. 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.