Interaction between Cardiac Calsequestrin and Drugs with Known Cardiotoxicity

Abstract

Ca2ϩ 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 heartrelated 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 Ca 2ϩ binding capacity of cCSQ was checked using equilibrium dialysis and atomic absorption spectroscopy, which clearly showed a significant reduction in Ca 2ϩ 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.

Amitriptyline Activates Cardiac Ryanodine Channels and Causes Spontaneous Sarcoplasmic Reticulum Calcium Release

“…Because AMT is known to bind to Casq2 (Park et al, 2005), and Casq2 prominently regulates RyR2 channel open probability (Gyorke et al, 2002), we investigated the possibility that Casq2 is the binding site responsible for the AMT induced channel opening we observe. Thus, we determined the effect of increasing cytoplasmic (i.e., cis) AMT concentration on RyR2 channels isolated from Casq2(ϩ/ϩ) and Casq2(Ϫ/Ϫ) mice in the presence of cis 2 mM ATP and 0.1 M Ca 2ϩ (diastolic [Ca 2ϩ ]) at a holding potential of 40 mV ( Fig.…”

Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca 2+ Leak Independent of Luminal Ca 2+ and Trigger Ventricular Arrhythmias in Mice

“…For example, a number of antidepressant, neuroleptic, and chemotherapeutic agents have been shown to bind to Casq2 in vitro. 28 Based on the results from the Casq2 ϩ/Ϫ mice, even a modest disruption of Casq2 function by drugs may result in clinically significant proarrhythmia. Thus, interactions with Casq2 may have contributed to the increased risk of sudden cardiac death associated with high doses of tricyclic antidepressants.…”

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression

“…Despite the prevalence and societal burden of depression, the treatments currently available and their clinical efficacy remain unsatisfactory (Malberg & Blendy, 2005). Various classes of antidepressant drugs, including monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and selective noradrenaline reuptake inhibitors (SNRIs), may induce serious side effects, such as cardiac toxicity, hypopiesia, sexual dysfunction, body weight gain, and sleep disorders (Antai-Otong, 2004;Baldwin et al, 2006;Khurana & Baudendistel, 2003;Park et al, 2005). Thus, the identification of affordable drugs with few side effects among traditional Chinese medicines has recently gained considerable interest for Chinese investigators.…”