Interaction between cardiac calsequestrin and drugs with known cardiotoxicity

Il Yeong Park, Eun Jung Kim, HaJeung Park, Kelly Fields, A. Dunker, ChulHee Kang

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 Kd 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.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalMolecular Pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Calsequestrin
Pharmaceutical Preparations
Tricyclic Antidepressive Agents
Anthracyclines
Cardiotoxicity
Trifluoperazine
Calorimetry
Thioredoxins
Bradycardia
Drug Interactions
Tachycardia
Antipsychotic Agents
Dialysis
Permeability
Spectrum Analysis
Electrocardiography
Nucleotides
Heart Failure
Binding Sites
Calcium

ASJC Scopus subject areas

  • Pharmacology

Cite this

Interaction between cardiac calsequestrin and drugs with known cardiotoxicity. / Park, Il Yeong; Kim, Eun Jung; Park, HaJeung; Fields, Kelly; Dunker, A.; Kang, ChulHee.

In: Molecular Pharmacology, Vol. 67, No. 1, 01.2005, p. 97-104.

Research output: Contribution to journalArticle

Park, Il Yeong ; Kim, Eun Jung ; Park, HaJeung ; Fields, Kelly ; Dunker, A. ; Kang, ChulHee. / Interaction between cardiac calsequestrin and drugs with known cardiotoxicity. In: Molecular Pharmacology. 2005 ; Vol. 67, No. 1. pp. 97-104.
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