Evolution of Excitation-Contraction Coupling

John James Mackrill, Holly Shiels

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


In mammalian cardiomyocytes, Ca2+ influx through L-type voltage- 5
gated Ca2+ channels (VGCCs) is amplified by release of Ca2+ via type 2 ryanodine receptors (RyR2) in the sarcoplasmic reticulum (SR): a process termed Ca2+- 7 induced Ca2+-release (CICR). In mammalian skeletal muscles, VGCCs play a distinct role as voltage-sensors, physically interacting with RyR1 channels to initiate Ca2+ release, in a mechanism termed depolarisation-induced Ca2+-release (DICR). In the current study, we surveyed the genomes of animals and their close relatives, to explore the evolutionary history of genes encoding three proteins pivotal for ECC: L-type VGCCs; RyRs; and a protein family that anchors intracellular organelles to plasma membranes, namely junctophilins (JPHs),. In agreement with earlier studies, we find that non-vertebrate eukaryotes either lack VGCCs, RyRs and JPHs; or contain a single homologue of each protein. Furthermore, the molecular features of these proteins that are essential for DICR are only detectable within vertebrates and not in any other taxonomic group. Consistent with earlier physiological and ultrastructural observations, this suggests that the CICR is the most basal form of ECC and that DICR is a vertebrate innovation. This development was accompanied by the appearance of multiple homologues of RyRs, VGCCs and junctophilins in vertebrates, thought to have arisen by ‘whole genome replication’ mechanisms. Subsequent gene duplications and losses have resulted in distinct assemblies of ECC components in different vertebrate clades, with striking examples being the apparent absence of RyR2 from amphibians, and the additional duplication events for all three ECC proteins in teleost fish. This is consistent with teleosts possessing the most derived mode of DICR, with their Cav1.1 VGCCs completely lacking in Ca2+ channel activity.
Original languageEnglish
Title of host publicationCalcium Signaling
EditorsMd. Shahidul Islam
PublisherSpringer Nature
Publication statusPublished - 14 Jun 2019

Publication series

NameAdvances in Experimental Medicine and Biology
PublisherSpringer International Publishing


  • Excitation-contraction coupling
  • Ryanodine receptor
  • Voltage-gated Ca2+ channel
  • Junctophilin
  • Evolution
  • Whole-genome duplication


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