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Regulation of ryanodine receptors by FK506 binding proteins

Mihail G Chelu1, Cristina I Danila, Charles P Gilman

  • 1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.

Trends in Cardiovascular Medicine
|September 29, 2004
PubMed

Insights

FK506 binding proteins (FKBPs) regulate ryanodine receptors (RyRs), crucial calcium channels in muscle. Dysfunctional FKBP modulation of RyR2 may cause heart rhythm disorders and failure, while FKBP12 issues could link to muscle diseases like malignant hyperthermia.

Area of Science:

  • Molecular Biology
  • Cardiovascular Physiology
  • Muscle Physiology

Background:

  • Ryanodine receptors (RyRs) are essential sarcoplasmic reticulum calcium channels for muscle contraction.
  • Mutations in RyR isoforms (RyR1, RyR2) are linked to serious muscle and heart diseases.
  • FK506 binding proteins (FKBPs), specifically FKBP12 and FKBP12.6, modulate RyR function.

Purpose of the Study:

  • To review the regulation of RyRs by FKBPs.
  • To explore the role of FKBP12.6 in cardiac conditions like CPVT, ARVD2, and heart failure.
  • To discuss FKBP12's impact on skeletal muscle and its potential involvement in MH and CCD.

Main Methods:

  • Literature review of studies on RyR function, mutations, and FKBP interactions.
  • Analysis of existing research linking FKBP modulation to muscle and cardiac pathologies.
  • Synthesis of evidence regarding the physiological and pathological roles of FKBPs in RyR regulation.

Main Results:

  • FKBPs stabilize the closed state of RyRs, ensuring proper channel function.
  • Defective FKBP12.6 modulation of RyR2 is implicated in catecholaminergic polymorphic ventricular arrhythmias (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and heart failure.
  • FKBP12 depletion affects skeletal muscle function, with potential links to malignant hyperthermia (MH) and central core disease (CCD).

Conclusions:

  • FKBP modulation is critical for RyR channel function and preventing muscle and cardiac diseases.
  • Further research into FKBP-RyR interactions may reveal new therapeutic targets for these conditions.
  • Understanding these molecular mechanisms is key to addressing the pathophysiology of RyR-associated disorders.

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