β subunits of voltage-gated calcium channels in cardiovascular diseases

Calcium signaling is required in bodily functions essential for survival, such as muscle contractions and neuronal communications. Of note, the voltage-gated calcium channels (VGCCs) expressed on muscle and neuronal cells, as well as some endocrine cells, are transmembrane protein complexes that allow for the selective entry of calcium ions into the cells. The alpha 1 subunit constitutes the main pore-forming subunit that opens in response to membrane depolarization, and its biophysical functions are regulated by various auxiliary subunits-beta, alpha 2 delta, and gamma subunits. Within the cardiovascular system, the gamma-subunit is not expressed and is therefore not discussed in this review. Because the alpha 1 subunit is the pore-forming subunit, it is a prominent druggable target and the focus of many studies investigating potential therapeutic interventions for cardiovascular diseases. While this may be true, it should be noted that the direct inhibition of the alpha 1 subunit may result in limited long-term cardiovascular benefits coupled with undesirable side effects, and that its expression and biophysical properties may depend largely on its auxiliary subunits. Indeed, the alpha 2 delta subunit has been reported to be essential for the membrane trafficking and expression of the alpha 1 subunit. Furthermore, the beta subunit not only prevents proteasomal degradation of the alpha 1 subunit, but also directly modulates the biophysical properties of the alpha 1 subunit, such as its voltage-dependent activities and open probabilities. More importantly, various isoforms of the beta subunit have been found to differentially modulate the alpha 1 subunit, and post-translational modifications of the beta subunits further add to this complexity. These data suggest the possibility of the beta subunit as a therapeutic target in cardiovascular diseases. However, emerging studies have reported the presence of cardiomyocyte membrane alpha 1 subunit trafficking and expression in a beta subunit-independent manner, which would undermine the efficacy of beta subunit-targeting drugs. Nevertheless, a better understanding of the auxiliary beta subunit would provide a more holistic approach when targeting the calcium channel complexes in treating cardiovascular diseases. Therefore, this review focuses on the post-translational modifications of the beta subunit, as well as its role as an auxiliary subunit in modulating the calcium channel complexes.

Automated summary

Calcium signaling plays a crucial role in essential bodily functions such as muscle contractions and neuronal communications. Voltage-gated calcium channels (VGCCs) are transmembrane protein complexes that allow for the selective entry of calcium ions into cells. The alpha 1 subunit constitutes the main pore-forming subunit and is regulated by various auxiliary subunits. Understanding the role of the beta subunit and its post-translational modifications is essential for developing therapeutic interventions for cardiovascular diseases.