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(Circulation Research. 2002;91:276.)
© 2002 American Heart Association, Inc.

Editorials

The Ca²⁺ Synapse Redo

A Matter of Location, Location, Location

Leighton T. Izu, C. William Balke

From the Departments of Physiology (C.W.B.) and Medicine (L.T.I., C.W.B.), School of Medicine, University of Maryland, Baltimore, Md.

Correspondence to C. William Balke, MD, University of Maryland School of Medicine, 22 S Greene St, S3B06, Baltimore, MD 21201–1595. E-mail bbalke@medicine.umaryland.edu

Key Words: excitation-contraction coupling • local control • sodium-calcium exchange • transverse tubules

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

The past decade has witnessed the evolution of a new paradigm in thinking about the intimate interrelationship between cellular structure and physiological function in biological processes. It is not surprising that this evolution has, perhaps, its clearest history in the field of excitation-contraction (E-C) coupling, which has had to wrestle with the long-standing paradox of how the release of Ca²⁺ from the sarcoplasmic reticulum (SR) can be graded by membrane potential¹ in the presence of regenerative Ca²⁺ release (Ca²⁺-induced Ca²⁺ release^2–4). In retrospect, it is clear that the resolution of this paradox had to await both methodological and theoretical breakthroughs that allowed researchers to change the scale of our measurements and thinking. Until the early 1990s, measurements of intracellular Ca²⁺ were limited to spatially averaged whole-cell Ca²⁺ transients or Ca²⁺ waves. The corresponding theoretical constructs assumed a spatially continuous distribution of SR Ca²⁺ release, which successfully predicted the properties of Ca²⁺ waves but precluded graded Ca²⁺ transients—hence the paradox.

In 1992, Stern⁵ made a key advance toward the resolution of this paradox by recognizing that all-or-nothing SR Ca²⁺ release could be avoided by having discrete Ca²⁺ release sites that were spatially segregated. This model was unique in that it included the intimate association or coupling of dihydropyridine receptors (DHPRs) to a discrete cluster of ryanodine receptors (RyRs), forming what he called a " Ca²⁺ synapse." In this model, each cluster of RyRs may release Ca²⁺ in an all-or-nothing manner, but because of their physical separation, each cluster could . . . [Full Text of this Article]