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(Circulation Research. 2001;88:134.)
© 2001 American Heart Association, Inc.

Editorials

Cardiac Ryanodine Receptors and Accessory Proteins: Augmented Expression Does Not Necessarily Mean Big Function

Héctor H. Valdivia

From the Department of Physiology, University of Wisconsin Medical School, Madison, Wis.

Correspondence to Héctor H. Valdivia, MD, PhD, Department of Physiology, University of Wisconsin Medical School, 1300 University Ave, Madison, WI 53706. E-mail valdivia@physiology.wisc.edu

Key Words: FKBP12 • excitation-contraction coupling • Ca²⁺-induced Ca²⁺ release • sarcoplasmic reticulum • immunophilin

	Introduction

 
In cardiac cells, depolarization of the external membrane and its infoldings, the T-tubules, opens voltage-sensitive Ca²⁺ channels/dihydropyridine receptors (DHPRs), allowing a small influx of extracellular Ca²⁺ (the inward Ca²⁺ current, I_Ca). In mature cardiomyocytes, I_Ca is insufficient to elevate myoplasmic [Ca²⁺] to fully contracting levels; however, I_Ca triggers the opening of Ca²⁺ release channels/ryanodine receptors (RyRs), which produce a rapid and massive release of Ca²⁺ from the sarcoplasmic reticulum (SR). This amplification process, termed Ca²⁺-induced Ca²⁺ release (CICR),¹ may be graded by endogenous effectors, hormones, and neurotransmitters to regulate the intensity and duration of ventricular contractions.²

RyRs are homotetramers of more than 2 megadaltons endowed with more than a fair share of structural elements to produce a bona fide ion channel. They contain a high-conductance Ca²⁺-selective pore, Ca²⁺ activation and inactivation sites, several phosphorylation sites, and multiple binding sites for a myriad of endogenous regulators that include ATP, Mg²⁺, and calmodulin.^{3 4} Still, as if this huge structural assembly were not sufficiently complex, RyRs are also capable of protein-protein interactions that allow them to bind, in some cases steadily and in other cases in a time- and Ca²⁺-dependent manner, to small and independently regulated accessory proteins.⁵ Therefore, although the RyR homotetramer with its intrinsic regulatory domains seems to be the central processor of effector signals, its association with cytosolic (FKBP12, sorcin, and calmodulin) and lumenal (calsequestrin, junctin, and triadin) proteins seems to add another layer of versatility (and complexity) to modulation of CICR in the . . . [Full Text of this Article]

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