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Direct Effects of Toxic Divalent Cations on Contractile Proteins with Implications for the Heart: Unraveling
Oksana P Gerzen1, Veronika O Votinova1, Iulia K Potoskueva1
1Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, 620049 Ekaterinburg, Russia.
Abstract:
The binding of calcium and magnesium ions to proteins is crucial for regulating heart contraction. However, other divalent cations, including xenobiotics, can accumulate in the myocardium and enter cardiomyocytes, where they can bind to proteins. In this article, we summarized the impact of these cations on myosin ATPase activity and EF-hand proteins, with special attention given to toxic cations. Optimal binding to EF-hand proteins occurs at an ionic radius close to that of Mg2+ and Ca2+. In skeletal Troponin C, Cd2+, Sr2+, Pb2+, Mn2+, Co2+, Ni2+, Ba2+, Mg2+, Zn2+, and trivalent lanthanides can substitute for Ca2+. As myosin ATPase is not a specific MgATPase, Ca2+, Fe2+, Mn2+, Ni2+, and Sr2+ could support myosin ATPase activity. On the other hand, Zn2+ and Cu2 significantly inhibit ATPase activity. The affinity to various divalent cations depends on certain proteins or their isoforms and can alter with amino acid substitution and post-translational modification. Cardiac EF-hand proteins and the myosin ATP-binding pocket are potential molecular targets for toxic cations, which could significantly alter the mechanical characteristics of the heart muscle at the molecular level.
Insights
Toxic cations can disrupt heart muscle function by binding to essential proteins like EF-hand proteins and myosin ATPase. This binding can alter cardiac contraction and mechanical properties at a molecular level.
Area of Science:
- Biochemistry
- Cardiology
- Toxicology
Background:
- Calcium (Ca2+) and magnesium (Mg2+) ions are vital for heart contraction by binding to proteins.
- Xenobiotic divalent cations can accumulate in cardiomyocytes and affect protein function.
Purpose of the Study:
- To summarize the impact of various divalent cations, particularly toxic ones, on myosin ATPase activity and EF-hand proteins.
- To identify potential molecular targets for toxic cations within cardiac muscle.
Main Methods:
- Review of existing literature on cation binding to cardiac proteins.
- Analysis of cation substitution in EF-hand proteins like Troponin C.
- Examination of effects of various cations on myosin ATPase activity.
Main Results:
- Optimal binding to EF-hand proteins occurs with ionic radii similar to Ca2+ and Mg2+.
- Several cations (Cd2+, Sr2+, Pb2+, Mn2+, Co2+, Ni2+, Ba2+, Mg2+, Zn2+, lanthanides) can substitute for Ca2+ in skeletal Troponin C.
- Myosin ATPase activity can be supported by Ca2+, Fe2+, Mn2+, Ni2+, and Sr2+, but inhibited by Zn2+ and Cu2+.
- Cation affinity varies based on protein isoforms, amino acid substitutions, and post-translational modifications.
Conclusions:
- Cardiac EF-hand proteins and the myosin ATP-binding pocket are susceptible to toxic cation binding.
- Toxic cations can significantly alter the mechanical properties of heart muscle at the molecular level.
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