Calmodulin and cyclic ADP-ribose interaction in Ca2+ signaling related to cardiac sarcoplasmic reticulum: superoxide anion radical-triggered Ca2+ release.
Reactive oxygen species (ROS) are often shown to damage cellular functions. The targets of oxidative damage depend on the nature of ROS produced and the site of generation. In contrast, ROS can also regulate signal transduction. In this case, ROS may either induce or enhance events, which lead to forward directions of cellular signaling. The consequences of regulation of signal transduction can be observed in physiological processes such as muscle contraction. Here, we discuss the concentration-dependent effects of superoxide anion radical (*O2-) on Ca2+ release from the cardiac sarcoplasmic reticulum (SR). Recent studies suggest that the ADP-ribosyl cyclase pathway, through its production of cyclic adenosine 5'-diphosphoribose (cADPR), may control Ca2+ mobilization in cardiac muscle cells. *O2- has dual effects that are concentration dependent. At low concentrations (nearly nanomolar levels), *O2- induces Ca2+ release by stimulating synthesis of cADPR, which requires calmodulin for sensitization of ryanodine-sensitive Ca2+-release channels (RyRC). At these low concentrations, *O2- is responsible for regulation of cellular signal transduction. At higher concentrations (micromolar levels), *O2- produces a loss in the function of calmodulin that is to inhibit RyRC. This results in an increase in Ca2+ release, which is linked to cell injury. The difference in the functions of low and high concentrations of *O2- may result in two distinct physiological roles in cardiac muscle Ca2+ signaling.
Okabe
E
E
Department of Pharmacology, Kanagawa Dental College, Yokosuka, Japan. okabe@kdcnet.ac.jp
Tsujimoto
Y
Y
Kobayashi
Y
Y
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002147:Calmodulin / Q000494:pharmacology / Q000502:physiology*; D036563:Cyclic ADP-Ribose; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009244:NAD+ Nucleosidase / Q000378:metabolism; D018384:Oxidative Stress; D011487:Protein Conformation / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D002147:Calmodulin; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013481:Superoxides; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1