Regulation of calcium release by interdomain interaction within ryanodine receptors.
In excitation-contraction (E-C) coupling, various types of activation signals, which are received presumably at the bulky cytoplasmic domain of the ryanodine receptor (RyR), are translated (or transduced) into the opening of the Ca2+ release channel located in the trans-membrane domain of the RyR. In order to elucidate the detailed mechanism of the signal transduction process, it is essential (i) to identify various sub-domains of the RyR that are involved in the Ca2+ channel regulation, (ii) to characterize the events occurring in these sub-domains during the activation process, and (iii) to characterize the modes of active interactions among these sub-domains. Recent developments in the E-C coupling research have provided us with new insight into each of these aspects, as outlined in this review. Of many putative regulatory sub-domains of the RyR, two domains (designated as N-terminal domain and central domain) are particularly interesting, because disease-linked mutations that have occurred in these domains (malignant hyperthermia and central core disease in skeletal muscle, and inheritable cardiac disease) induce abnormal modes of Ca2+ channel regulation. Pieces of evidence accumulated to this date suggest the following hypothesis. The N-terminal and central domains form, at least partly, the interacting domain pair, and unzipping and zipping actions of such domain-pair are involved in the opening and closing actions of the Ca2+ channel, respectively. We also propose that there are local conformational changes in the signal reception domains (e.g. the II-III loop-binding core), and such conformational changes are coupled with the aforementioned actions of the interacting domain pair. It seems that by virtue of such a coordination of the events occurring in various regions of the RyR, the Ca2+ channel can recognize the activation signal received at the cytoplasmic region of the RyR.
Ikemoto
Noriaki
N
Boston Biomedical Research Institute, Watertown, MA 02472, USA. ikemoto@bbri.org
Yamamoto
Takeshi
T
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009119:Muscle Contraction / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium