RT Journal Article
SR Electronic
T1 Pharmacological regulation of endoplasmic reticulum structure and calcium dynamics: importance for neurodegenerative diseases
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP PHARMREV-AR-2022-000701
DO 10.1124/pharmrev.122.000701
A1 Ilmari Parkkinen
A1 Anna Their
A1 Muhammad Yasir Asghar
A1 Sreesha Sree
A1 Eija Jokitalo
A1 Mikko Airavaara
YR 2023
UL http://pharmrev.aspetjournals.org/content/early/2023/05/01/pharmrev.122.000701.abstract
AB The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca2+) and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, also for synaptic signaling and Ca2+ waves, as well as preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiological functions of the neuronal ER and discuss it in context of common neurodegenerative diseases focusing on pharmacological regulation of ER Ca2+. Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity and ensuring Ca2+ regulation is a crucial factor for the aging and selective vulnerability of neurons in various neurodegenerative diseases. Significance Statement ER Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis, e.g. folding of complex plasma membrane signalling receptors and slow down the degeneration process of neurons.