Post-Translational Modification of Cav1.2 and its Role in Neurodegenerative Diseases

Abstract

Cav1.2 plays an essential role in learning and memory, drug addiction, and neuronal development. Intracellular calcium homeostasis is disrupted in neurodegenerative diseases because of abnormal Cav1.2 channel activity and modification of downstream Ca2+ signaling pathways. Multiple post-translational modifications of Cav1.2 have been observed and seem to be closely related to the pathogenesis of neurodegenerative diseases. The specific molecular mechanisms by which Cav1.2 channel activity is regulated remain incompletely understood. Dihydropyridines (DHPs), which are commonly used for hypertension and myocardial ischemia, have been repurposed to treat PD and AD and show protective effects. However, further studies are needed to improve delivery strategies and drug selectivity. Better knowledge of channel modulation and more specific methods for altering Cav1.2 channel function may lead to better therapeutic strategies for neurodegenerative diseases.

Modulation of L-type calcium channels in Alzheimer’s disease: A potential therapeutic target

“…This suggests that the hippocampus, a primary memory center of the brain, is more vulnerable to calcium dysregulation in AD [33] . LTCC blockers have shown beneficial effects in reversing neuronal dysfunction and cognitive impairment in both humans and animal models [34] , [43] , [97] .…”

MicroRNAs – small RNAs with a big influence on brain excitability

“…VGCC β‐subunits enhance channel function via modulation of channel gating and kinetics, as well as enhanced trafficking of VGCCs from the endoplasmic reticulum to the cell surface (Bichet et al., 2000). Cav1.2 is the major VGCC isoform in neurons (Li et al., 2022) and so is a critical route for calcium influx in response to depolarisation, and therefore underlies key physiological processes which include NMDA receptor‐independent plasticity (Moosmang et al., 2005), memory (Li et al., 2022; Moosmang et al., 2005) and activation of intracellular signalling pathways which can modulate gene expression (Dolmetsch, 2003).…”

Role of posttranslational modifications in memory and cognitive impairments caused by neonatal sevoflurane exposure

“…The creation of phosphodiester bonds can occur on the side chains of serine, threonine and tyrosine (often referred to as “residues”). Numerous protein kinases, protein phosphatases, and phosphorylated proteins are found in neurons, and many of these are crucial for controlling neuronal morphology and for a variety of cell processes, including membrane excitability, secretory procedures, cytoskeletal organization, and cellular metabolism ( Li et al, 2021 ).…”