EXCITATION–CONTRACTION COUPLING FROM THE 1950s INTO THE NEW MILLENNIUM
This paper derives from the AuPS invited lecture presented at the 2005 joint meeting of AuPS and the Australian Biophysics Society. It has been peer reviewed and revised in the light of the reviews and comments from the AuPS editor. It has been published in the AuPS on-line proceedings (http://www.aups.org.au/Proceedings).
Professor AF Dulhunty, Division of Molecular Bioscience, John Curtin School of Medical Research, Building 54, Off Mills Road, Australian National University, ACT 0200, Australia. Email: firstname.lastname@example.org
- 1Excitation–contraction coupling is broadly defined as the process linking the action potential to contraction in striated muscle or, more narrowly, as the process coupling surface membrane depolarization to Ca2+ release from the sarcoplasmic reticulum.
- 2We now know that excitation–contraction coupling depends on a macromolecular protein complex or ‘calcium release unit’. The complex extends the extracellular space within the transverse tubule invaginations of the surface membrane, across the transverse tubule membrane into the cytoplasm and then across the sarcoplasmic reticulum membrane and into the lumen of the sarcoplasmic reticulum.
- 3The central element of the macromolecular complex is the ryanodine receptor calcium release channel in the sarcoplasmic reticulum membrane. The ryanodine receptor has recruited a surface membrane L-type calcium channel as a ‘voltage sensor’ to detect the action potential and the calcium-binding protein calsequestrin to detect in the environment within the sarcoplasmic reticulum. Consequently, the calcium release channel is able to respond to surface depolarization in a manner that depends on the Ca2+ load within the calcium store.
- 4The molecular components of the ‘calcium release unit’ are the same in skeletal and cardiac muscle. However, the mechanism of excitation–contraction coupling is different. The signal from the voltage sensor to ryanodine receptor is chemical in the heart, depending on an influx of external Ca2+ through the surface calcium channel. In contrast, conformational coupling links the voltage sensor and the ryanodine receptor in skeletal muscle.
- 5Our current understanding of this amazingly efficient molecular signal transduction machine has evolved over the past 50 years. None of the proteins had been identified in the 1950s; indeed, there was debate about whether the molecules involved were, in fact, protein. Nevertheless, a multitude of questions about the molecular interactions and structures of the proteins and their interaction sites remain to be answered and provide a challenge for the next 50 years.