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Triadin: the new player on excitation-contraction coupling block.

See related article, pages 651–658 

The Ca2+ movements that control many cellular functions, including contraction of striated and smooth muscle cells and vesicular secretion from endocrine cells and nerve terminals, are increasingly recognized to involve macromolecular Ca2+-signaling complexes that, in addition to the key Ca2+-transporting proteins, include large numbers of associated proteins that provide a variety of regulatory, structural and Ca2+-sensing/buffering functions. The importance of working out the subtle interactions within these macromolecular complexes is underscored by the genetic diseases that have been associated with mutations of their constituent proteins.

In this issue, Terentyev et al1 use a spectrum of molecular and electrophysiological techniques to demonstrate that triadin (TRD) plays an unexpectedly important role in regulating the ryanodine receptors (RyRs), found primarily in dyadic junctions of cardiac sarcoplasmic reticulum (SR; Figure). It has been previously suggested that TRD and junctin are integral membrane proteins of the junctional SR, and serve as linker proteins from the SR Ca release channel (RyR) to calsequestrin (CSQ) complexes, the major Ca2+-buffer in the lumen of the SR (Figure).2 The large (≈4500 aa) cytoplasmic domain of RyR appears to have multiple binding sites for an ever-growing list of proteins that includes: calmodulin, PKA, FKBP 12.6.3 The major findings of the present communication are that overexpression of TRD leads to 3-fold increase in open probability of RyRs in bilayers, a 60% increase in spontaneous spark frequency with only minor decreases in spark amplitude (≈10%) and SR Ca2+ content (≈30%), as well as a marked alteration in the voltage dependence of Ca2+ release. The authors propose the activity of RyRs to be directly modulated by the level of expression of TRD, most likely mediated by amino acid residues 200 to 224 …