Xander H.T. Wehrens, MD, PhD, Andrew R. Marks, MD

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Presentation transcript:

Sudden Unexplained Death Caused by Cardiac Ryanodine Receptor (RyR2) Mutations Xander H.T. Wehrens, MD, PhD, Andrew R. Marks, MD Mayo Clinic Proceedings Volume 79, Issue 11, Pages 1367-1371 (November 2004) DOI: 10.4065/79.11.1367 Copyright © 2004 Mayo Foundation for Medical Education and Research Terms and Conditions

FIGURE 1 Physiological regulation of the ryanodine receptor (RyR2) macromolecular complex. A, The RyR2 macromolecular complex includes 4 identical RyR2 subunits (orange, numbers 1 through 4 indicate the 4 monomers). Each RyR2 subunit binds one calstabin2 (FKBP12.6, yellow triangle), as well as the protein kinase A (PKA) catalytic and regulatory subunits (RII) (purple), muscle A-kinase anchoring protein (mAKAP) (purple), protein phosphatase 2A (PP2A) and its targeting protein PR130 (gray), and protein phosphatase 1 (PP1) and its targeting protein sphinophilin (green). (For clarity reasons, accessory molecules are shown only for 1 of the 4 RyR2 subunits, except for calstabin2, which is shown for all 4 RyR2 subunits.) B, In normal hearts, exercise activates the β-adrenergic signaling pathway, leading to activation of PKA, increased calcium (Ca2+) release through RyR2, and improved cardiac contractility. Protein kinase A phosphorylation of RyR2 leads to phosphorylation of 1 to 2 (of 4) serine 2809 (Ser2809) amino acids, which causes dissociation of 1 to 2 (of 4) calstabin2 molecules from the RyR2 complex. During exercise, the RyR2 complex remains closed during diastole. C, In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited RyR2 mutation reduces the calstabin2-binding affinity for RyR2. After exercise, 2 to 4 calstabin2 molecules are released from the channel complex, leading to increased Ca2+-dependent activation and release of Ca2+ from the sarcoplasmic reticulum (SR) during diastole (Leak) that can activate depolarizations and trigger fatal ventricular arrhythmias. Modified from Trends Biochem Sci,22 with permission from Elsevier Health Sciences. Mayo Clinic Proceedings 2004 79, 1367-1371DOI: (10.4065/79.11.1367) Copyright © 2004 Mayo Foundation for Medical Education and Research Terms and Conditions