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Interaction between Cardiac Calsequestrin and Drugs with Known Cardiotoxicity

School of Molecular Biosciences, Washington State University, Pullman, Washington (I.Y.P., E.J.K., H.P., K.F., C.K.); and Center for Computational Biology and Informatics and the Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana (K.A.D.)

Ca²⁺ regulation is coupled to critical signals in eucaryotic cells, and calsequestrin is one of the crucial components for this calcium regulation. Our previous observations of calsequestrins revealed the existence of three thioredoxin-like folds, a basic motif that often provides the platform for small molecule binding. Therefore, we have examined the previously reported trifluoperazine and other pharmaceuticals that have similar heart-related side effects (such as tachycardia; bradycardia; palpitation; changing PR, QRS, QTc intervals in electrocardiogram; heart failure) for their binding affinity to cardiac calsequestrin (cCSQ) using isothermal titration calorimetry. Our results showed that several antipsychotic phenothiazine derivatives, tricyclic antidepressants, and anthracycline derivatives bind cCSQ with K_d in the micromolar range. For these compounds that have a significantly low K_d, their effect on Ca²⁺ binding capacity of cCSQ was checked using equilibrium dialysis and atomic absorption spectroscopy, which clearly showed a significant reduction in Ca²⁺ binding capacity of cCSQ as a result of this interaction. Furthermore, 8-anilino-1-naphthalene sulfonate (ANS) binding to cCSQ closely resembles ANS binding to flavine or nucleotide binding sites. The combination of this information with the high abundance of CSQ in SR and the high membrane permeability of those drugs led us to the specific hypothesis that there are undesirable and damaging interactions between cCSQ and tricyclic antidepressants, phenothiazine derivatives, anthracyclines, and many other pharmaceutical compounds and to the corollary hypothesis that better understanding of the molecular details of cCSQ-drug interactions could lead to modified drug molecules with reduced heart-related side effects.

Address correspondence to: Dr. ChulHee Kang, 264 Fulmer, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660. E-mail: chkang{at}wsunix.wsu.edu

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