Ryanodine Receptors in Autophagy: Implications for Neurodegenerative Diseases?

Intracellular Ca²⁺ signaling is important in the regulation of several cellular processes including autophagy. The endoplasmic reticulum (ER) is the main and largest intracellular Ca²⁺ store. At the ER two protein families of Ca²⁺ release channels, inositol 1,4,5-trisphosphate receptors (IP₃Rs) and ryanodine receptors (RyRs), are expressed. Several studies have reported roles in the regulation of autophagy for the ubiquitously expressed IP₃R. For instance, IP₃R-mediated Ca²⁺ release supresses basal autophagic flux by promoting mitochondrial metabolism, while also promoting the rapid initial increase in autophagic flux in response to nutrient starvation. Insights into the contribution of RyRs in autophagy have been lagging significantly compared to the advances made for IP₃Rs. This is rather surprising considering that RyRs are predominantly expressed in long-lived cells with specialized metabolic needs, such as neurons and muscle cells, in which autophagy plays important roles. In this review article, recent studies revealing roles for RyRs in the regulation of autophagy will be discussed. Several RyR-interacting proteins that have been established to modulate both RyR function and autophagy will also be highlighted. Finally, the involvement of RyRs in neurodegenerative diseases will be addressed. Inhibition of RyR channels has not only been shown to be beneficial for treating several of these diseases but also regulates autophagy.