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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.

SUBMITTER: Li Y

PROVIDER: S-EPMC8802068 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sirtuins are protein deacetylases that play a protective role in cardiovascular diseases (CVDs), as well as many other diseases. Absence of sirtuins can lead to hyperacetylation of both nuclear and mitochondrial proteins leading to metabolic dysregulation. The protein post-translational modifications (PTMs) are known to crosstalk among each other to bring about complex phenotypic outcomes. Various PTM types such as acetylation, ubiquitination, and phosphorylation, and so on, drive transcriptional regulation and metabolism, but such crosstalks are poorly understood. We integrated protein-protein interactions (PPI) and PTMs from several databases to integrate information on 1,251 sirtuin-interacting proteins, of which 544 are associated with cardiac diseases. Based on the ?100,000 PTM sites obtained for sirtuin interactors, we observed that the frequency of PTM sites (83 per protein), as well as PTM types (five per protein), is higher than the global average for human proteome. We found that ?60-70% PTM sites fall into ordered regions. Approximately 83% of the sirtuin interactors contained at least one competitive crosstalk (in situ) site, with half of the sites occurring in CVD-associated proteins. A large proportion of identified crosstalk sites were observed for acetylation and ubiquitination competition. We identified 614 proteins containing PTM hotspots (?5 PTM sites) and 133 proteins containing crosstalk hotspots (?3 crosstalk sites). We observed that a large proportion of disease-associated sequence variants were found in PTM motifs of CVD proteins. We identified seven proteins (TP53, LMNA, MAPT, ATP2A2, NCL, APEX1, and HIST1H3A) containing disease-associated variants in PTM and crosstalk hotspots. This is the first comprehensive bioinformatics analysis on sirtuin interactors with respect to PTMs and their crosstalks. This study forms a platform for generating interesting hypotheses that can be tested for a deeper mechanistic understanding gained or derived from big-data analytics.

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

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