Functional maintenance of calcium store by ShcB adaptor protein in cerebellar Purkinje cells

Intracellular Ca²⁺ levels are changed by influx from extracellular medium and release from intracellular stores. In the central nervous systems, Ca²⁺ release is involved in various physiological events, such as neuronal excitability and transmitter release. Although stable Ca²⁺ release in response to stimulus is critical for proper functions of the nervous systems, regulatory mechanisms relating to Ca²⁺ release are not fully understood in central neurons. Here, we demonstrate that ShcB, an adaptor protein expressed in central neurons, has an essential role in functional maintenance of Ca²⁺ store in cerebellar Purkinje cells (PCs). ShcB-knockout (KO) mice showed defects in cerebellar-dependent motor function and long-term depression (LTD) at cerebellar synapse. The reduced LTD was accompanied with an impairment of intracellular Ca²⁺ release. Although the expression of Ca²⁺ release channels and morphology of Ca²⁺ store looked intact, content of intracellular Ca²⁺ store and activity of sarco/endoplasmic reticular Ca²⁺-ATPase (SERCA) were largely decreased in the ShcB-deficient cerebellum. Furthermore, when ShcB was ectopically expressed in the ShcB-KO PCs, the Ca²⁺ release and its SERCA-dependent component were restored. These data indicate that ShcB plays a key role in the functional maintenance of ER Ca²⁺ store in central neurons through regulation of SERCA activity.