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

Intracellular Ca(2+) levels are changed by influx from extracellular medium and release from intracellular stores. In the central nervous systems, Ca(2+) release is involved in various physiological events, such as neuronal excitability and transmitter release. Although stable Ca(2+) release in response to stimulus is critical for proper functions of the nervous systems, regulatory mechanisms relating to Ca(2+) 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 Ca(2+) 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 Ca(2+) release. Although the expression of Ca(2+) release channels and morphology of Ca(2+) store looked intact, content of intracellular Ca(2+) store and activity of sarco/endoplasmic reticular Ca(2+)-ATPase (SERCA) were largely decreased in the ShcB-deficient cerebellum. Furthermore, when ShcB was ectopically expressed in the ShcB-KO PCs, the Ca(2+) release and its SERCA-dependent component were restored. These data indicate that ShcB plays a key role in the functional maintenance of ER Ca(2+) store in central neurons through regulation of SERCA activity.