Subcellular localization and transcriptional regulation of brain ryanodine receptors. Functional implications

Ryanodine receptors (RyR) are intracellular Ca²⁺ channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca²⁺-induced Ca²⁺ calcium release (CICR). In the brain, mammals express in both neurons, and non-neuronal cells, a combination of the three RyR-isoforms (RyR1-3). Pharmacological approaches, which do not distinguish between isoforms, have indicated that RyR-isoforms contribute to brain function. However, isoform-specific manipulations have revealed that RyR-isoforms display different subcellular localizations and are differentially associated with neuronal function. These findings raise the need to understand RyR-isoform specific transcriptional regulation, as this knowledge will help to elucidate the causes of neuronal dysfunction for a growing list of brain disorders that show altered RyR channel expression and function.