ATP2B2 and Associated Diseases

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Background of ATP2B2

The regulation of intracellular calcium plays an important role in eukaryotic cells. The plasma membrane Ca²⁺ ATPase (PMCA pump) regulates the Ca²⁺ concentration gradients and maintains intracellular calcium homeostasis. PMCA pump is divided into four isoforms in mammals. The ATP2B2 gene encodes isoform 2, which is located on chromosome 3p and is primarily expressed in the central nervous system and salivary gland. PMCA isoform 2 is able to bind ATP, proteins, metal ions, glutamate receptors, the PDZ domain, and calmodulin. It activates the ATPase-coupled cation transporter and P-type calcium transporter to regulate postsynaptic cytosolic calcium ion concentration. As it is greatly expressed in the brain, the ATP2B2 gene is involved in the development of the brain and neural retina, neuron differentiation, and sensory perception of sound. Besides, it participates in calcium ion transmembrane transport and regulation of cardiac conduction.

ATP2B2 Associated Diseases

A V1143F substitution in the neuronal-enriched isoform 2 of the PMCA pump changes the binding of calmodulin to the calmodulin-binding domain, which impairs the function of Ca²⁺ ejection, and thus causes ataxia. PMCA isoform 2 is also involved in the protein kinase C (PKC)-gamma calcium signaling pathway in ataxia. In addition, the dysfunction of PMCA isoform 2 caused by de novo and inherited variants of ATP2B2 is related to rapidly progressive hearing impairment, as the PMCA2w/a pump plays a crucial role in controlling the hair cell mechanotransduction, auditory function, and survival. Furthermore, the mutations of the ATP2B2 gene alter the function of PMCA isoform 2, which mediates the human epidermal growth factor receptor 2 (HER2) signaling and membrane retention in breast cancers.

Fig.1 Schematics of the hair cell stereociliary bundle in the resting and deflected state. (Bortolozzi, 2018)

A number of diseases are related to ATP2B2 mutations. The pathogenesis of the disorders associated with ATP2B2 will be the focus of future attempts to develop gene therapies. Innovative biotech firm Creative Biolabs is dedicated to offering top-notch products and services for gene therapy development. Our group offers researchers from all over the world cutting-edge support expertise on ATP2B2 and associated diseases. We are happy to offer our expertise and technology to meet your project’s requirements. If you would want additional details about the ATP2B2 gene and associated diseases, please don't hesitate to contact us.

Reference

1. Bortolozzi, M.; Mammano, F. PMCA2 pump mutations and hereditary deafness. Neuroscience Letters. 2018, 663: 18-24.