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(Circulation Research. 2007;100:296.)
© 2007 American Heart Association, Inc.

Editorials

CaM or cAMP

Linking ß-Adrenergic Stimulation to ‘Leaky’ RyRs

Karin R. Sipido

From the Laboratory of Experimental Cardiology, University of Leuven, Belgium.

Correspondence to Karin R. Sipido, MD, PhD, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido@med.kuleuven.ac.be

See related article, pages 391–398

Key Words: Ca-calmodulin kinase • sarcoplasmic reticulum • heart failure • arrhythmias • ryanodine receptor • adrenergic receptor

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
During each heart beat a transient rise in [Ca²⁺]_i links the electrical signal to the actual contraction. Ca²⁺ release from the sarcoplasmic reticulum (SR) is the major source of this Ca²⁺ transient and occurs through the ryanodine receptor, RyR. The RyR is a Ca²⁺-activated channel, responding to Ca²⁺ influx, commonly referred to as the trigger Ca²⁺, predominantly through the L-type Ca²⁺ channel. The Ca²⁺ available in the SR is the SR Ca²⁺ content or Ca²⁺ load. The SR Ca²⁺ content depends to a large extent on the Ca²⁺ uptake into the SR by SERCA, regulated by phospholamban, and also on the balance of Ca²⁺ fluxes across the sarcolemma. For the latter, the Na⁺/Ca²⁺ exchanger is the major efflux pathway, generating an inward current. Alterations in [Ca²⁺]_i handling have been implicated in contractile dysfunction in heart failure, and several proteins are involved such as SERCA, phospholamban and the Na⁺/Ca²⁺ exchanger, which would all influence the available Ca²⁺ in the SR.

When Marks et al reported in 2000 that hyperphosphorylation of the ryanodine receptor (RyR) could underlie abnormal calcium cycling in heart failure,¹ it was the start of a new area of research that has since sparked a lot of debate. Increased phosphorylation was proposed to lead to reduced binding of the stabilizing protein, FKBP12.6 or calstabin, and result in increased channel openings or ‘leaky’ RyRs. This will lead to abnormal release of Ca²⁺ in diastole as well as abnormal gating during excitation-contraction coupling. The abnormal . . . [Full Text of this Article]

Related Article:

ß-Adrenergic Enhancement of Sarcoplasmic Reticulum Calcium Leak in Cardiac Myocytes Is Mediated by Calcium/Calmodulin-Dependent Protein Kinase

Jerald Curran, Mark J. Hinton, Eduardo Ríos, Donald M. Bers, and Thomas R. Shannon
Circ. Res. 2007 100: 391-398. [Abstract] [Full Text] [PDF]

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